Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Discovery Sciences, Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden.
Elife. 2022 Mar 1;11:e73777. doi: 10.7554/eLife.73777.
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.
肠道微生物群从不可消化的淀粉代谢中释放出的挥发性小分子，包括短链脂肪酸（SCFAs）、乙酸盐和丙酸盐，可以通过特定的 G 蛋白偶联受体（GPCR）发挥类似激素的作用。这些 SCFAs 的主要 GPCR 靶标是 FFA2 和 FFA3。使用转基因小鼠，其中 FFA2 被一种称为 Designer Receptor Exclusively Activated by Designer Drugs（FFA2-DREADD）的改变形式所取代，但 FFA3 未被改变，以及一种新发现的 FFA2-DREADD 激动剂 4-甲氧基-3-甲基苯甲酸（MOMBA），我们证明了 FFA2 和 FFA3 的特定功能如何定义 SCFA-肠道-大脑轴。肠道腔中 FFA2/3 的激活刺激脊髓活动，并且肠道 FFA3 的直接调节感觉传入神经元的发射。此外，我们证明 FFA2 和 FFA3 在背根神经节和结状神经节中均有功能性表达，它们通过不同的 G 蛋白和机制信号传导来调节细胞钙水平。我们得出结论，FFA2 和 FFA3 在不同的水平上发挥作用，为源自肠道微生物群的 SCFAs 可以调节中枢活动提供了一个轴。
