Chemogenetics defines a short-chain fatty acid receptor gut-brain axis.
Chemogenetics defines a short-chain fatty acid receptor gut-brain axis.
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化学遗传学定义了短链脂肪酸受体肠脑轴。
DOI：
10.7554/elife.73777
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发表时间：
2022-03-01
期刊：
影响因子：
7.7
通讯作者：
Milligan G
中科院分区：
文献类型：
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作者：
Barki N;Bolognini D;Börjesson U;Jenkins L;Riddell J;Hughes DI;Ulven T;Hudson BD;Ulven ER;Dekker N;Tobin AB;Milligan G
挥发性小分子，包括短链脂肪酸（SCFAs），乙酸酯和丙酸酯，由肠道微生物群从不易消化的淀粉中释放出来，可以通过特定的G蛋白偶联受体（GPCR）以类似葡萄糖的方式发挥作用。这些SCFA的主要GPCR靶标是FFA 2和FFA 3。使用转基因小鼠，其中FFA 2被称为设计师受体独家激活的设计师药物（FFA 2-DREADD）的改变形式所取代，但其中FFA 3未改变，以及新鉴定的FFA 2-DREADD激动剂4-甲氧基-3-甲基-苯甲酸（MOMBA），我们展示了FFA 2和FFA 3的特定功能如何定义SCFA-肠-脑轴。肠腔中FFA 2/3的激活刺激脊髓活动，肠FFA 3的激活直接调节感觉传入神经元放电。此外，我们证明，FFA 2和FFA 3都在背根和结状神经节中功能性表达，它们通过不同的G蛋白和机制来调节细胞钙水平。我们的结论是，FFA 2和FFA 3，在不同的水平上发挥作用，提供了一个轴，来自肠道微生物群的SCFA可以调节中枢活动。
Volatile small molecules, including the short-chain fatty acids (SCFAs), acetate and propionate, released by the gut microbiota from the catabolism of nondigestible starches, can act in a hormone-like fashion via specific G-protein-coupled receptors (GPCRs). The primary GPCR targets for these SCFAs are FFA2 and FFA3. Using transgenic mice in which FFA2 was replaced by an altered form called a Designer Receptor Exclusively Activated by Designer Drugs (FFA2-DREADD), but in which FFA3 is unaltered, and a newly identified FFA2-DREADD agonist 4-methoxy-3-methyl-benzoic acid (MOMBA), we demonstrate how specific functions of FFA2 and FFA3 define a SCFA–gut–brain axis. Activation of both FFA2/3 in the lumen of the gut stimulates spinal cord activity and activation of gut FFA3 directly regulates sensory afferent neuronal firing. Moreover, we demonstrate that FFA2 and FFA3 are both functionally expressed in dorsal root- and nodose ganglia where they signal through different G proteins and mechanisms to regulate cellular calcium levels. We conclude that FFA2 and FFA3, acting at distinct levels, provide an axis by which SCFAs originating from the gut microbiota can regulate central activity.