Shackley Matilda, Ma Yue, Tate Edward W, Brown Alastair J H, Frost Gary, Hanyaloglu Aylin C
Section of Nutrition Research, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, United Kingdom.
Institute of Reproductive and Developmental Biology, Department of Metabolism, Digestion, and Reproduction, Imperial College London, London, United Kingdom.
Front Nutr. 2020 Oct 29;7:568991. doi: 10.3389/fnut.2020.568991. eCollection 2020.
The short chain fatty acids (SCFAs) acetate, butyrate and propionate, are produced by fermentation of non-digestible carbohydrates by the gut microbiota and regulate appetite, adiposity, metabolism, glycemic control, and immunity. SCFAs act at two distinct G protein coupled receptors (GPCRs), FFAR2 and FFAR3 and are expressed in intestinal enteroendocrine cells (EECs), where they mediate anorectic gut hormone release. EECs also express other GPCRs that act as nutrient sensors, thus SCFAs may elicit some of their health-promoting effects by altering GPCR expression in EECs and enhance gut sensitivity to dietary molecules. Here, we identify that exposure of the murine EEC STC-1 cell line or intestinal organoids to physiological concentrations of SCFAs enhances mRNA levels of the umami taste receptors TASR1 and TASR3, without altering levels of the SCFA GPCRs, FFAR2 and FFAR3. Treatment of EECs with propionate or butyrate, but not acetate, increased levels of umami receptor transcripts, while propionate also reduced CCK expression. This was reversed by inhibiting Gαi/o signaling with pertussis toxin, suggesting that SCFAs act through FFAR2/3 to alter gene expression. Surprisingly, neither a FFAR3 nor a FFAR2 selective ligand could increase TASR1/TASR3 mRNA levels. We assessed the functional impact of increased TASR1/TASR3 expression using unique pharmacological properties of the umami taste receptor; namely, the potentiation of signaling by inosine monophosphate. Activation of umami taste receptor induced inositol-1-phosphate and calcium signaling, and butyrate pretreatment significantly enhanced such signaling. Our study reveals that SCFAs may contribute to EEC adaptation and alter EEC sensitivity to bioactive nutrients.
短链脂肪酸（SCFAs），即乙酸、丁酸和丙酸，由肠道微生物群对不可消化的碳水化合物进行发酵产生，可调节食欲、肥胖、新陈代谢、血糖控制和免疫。SCFAs作用于两种不同的G蛋白偶联受体（GPCRs），即FFAR2和FFAR3，并在肠道肠内分泌细胞（EECs）中表达，在这些细胞中它们介导厌食性肠道激素的释放。EECs还表达其他作为营养传感器的GPCRs，因此SCFAs可能通过改变EECs中GPCRs的表达来发挥其一些促进健康的作用，并增强肠道对饮食分子的敏感性。在这里，我们发现，将小鼠EEC STC-1细胞系或肠道类器官暴露于生理浓度的SCFAs下，可提高鲜味味觉受体TASR1和TASR3的mRNA水平，但不会改变SCFA GPCRs即FFAR2和FFAR3的水平。用丙酸或丁酸而非乙酸处理EECs，可增加鲜味受体转录本的水平，而丙酸还可降低胆囊收缩素（CCK）的表达。用百日咳毒素抑制Gαi/o信号传导可逆转这种情况，这表明SCFAs通过FFAR2/3发挥作用来改变基因表达。令人惊讶的是，无论是FFAR3选择性配体还是FFAR2选择性配体都不能增加TASR1/TASR3的mRNA水平。我们利用鲜味味觉受体独特的药理特性评估了TASR1/TASR3表达增加的功能影响；即肌苷单磷酸对信号传导的增强作用。鲜味味觉受体的激活诱导了肌醇-1-磷酸和钙信号传导，丁酸预处理显著增强了这种信号传导。我们的研究表明，SCFAs可能有助于EEC适应并改变EEC对生物活性营养素的敏感性。
