A balanced intake of macronutrients—protein, carbohydrate and fat—is essential for the well-being of organisms. An adequate calorific intake but with insufficient protein consumption can lead to several ailments, including kwashiorkor¹. Taste receptors (T1R1–T1R3)² can detect amino acids in the environment, and cellular sensors (Gcn2 and Tor)³ monitor the levels of amino acids in the cell. When deprived of dietary protein, animals select a food source that contains a greater proportion of protein or essential amino acids (EAAs)⁴. This suggests that food selection is geared towards achieving the target amount of a particular macronutrient with assistance of the EAA-specific hunger-driven response, which is poorly understood. Here we show in Drosophila that a microbiome–gut–brain axis detects a deficit of EAAs and stimulates a compensatory appetite for EAAs. We found that the neuropeptide CNMamide (CNMa)⁵ was highly induced in enterocytes of the anterior midgut during protein deprivation. Silencing of the CNMa–CNMa receptor axis blocked the EAA-specific hunger-driven response in deprived flies. Furthermore, gnotobiotic flies bearing an EAA-producing symbiotic microbiome exhibited a reduced appetite for EAAs. By contrast, gnotobiotic flies with a mutant microbiome that did not produce leucine or other EAAs showed higher expression of CNMa and a greater compensatory appetite for EAAs. We propose that gut enterocytes sense the levels of diet- and microbiome-derived EAAs and communicate the EAA-deprived condition to the brain through CNMa.

均衡摄入大量营养素——蛋白质、碳水化合物和脂肪——对生物体的健康至关重要。热量摄入充足但蛋白质摄入不足会导致多种疾病，包括 kwashiorkor ¹。味觉受体 (T1R1–T1R3) ²可以检测环境中的氨基酸，而细胞传感器（Gcn2 和 Tor）³则监测细胞中氨基酸的水平。当缺乏膳食蛋白质时，动物会选择含有更多蛋白质或必需氨基酸 (EAA) 的食物来源⁴. 这表明食物选择旨在在 EAA 特定的饥饿驱动反应的帮助下实现特定常量营养素的目标量，对此知之甚少。在这里，我们在果蝇中展示微生物组-肠-脑轴检测到 EAAs 的缺乏并刺激对 EAAs 的补偿性食欲。我们发现神经肽 CNMamide (CNMa) ⁵在蛋白质剥夺期间，在中肠前部的肠细胞中高度诱导。CNMa-CNMa 受体轴的沉默阻断了被剥夺果蝇的 EAA 特异性饥饿驱动反应。此外，携带产生 EAA 的共生微生物组的无菌果蝇表现出对 EAA 的食欲降低。相比之下，具有不产生亮氨酸或其他 EAAs 的突变微生物组的无菌果蝇表现出更高的 CNMa 表达和对EAAs更大的补偿性食欲。我们建议肠道细胞感知饮食和微生物组衍生的 EAA 水平，并通过 CNMa 将缺乏 EAA 的情况传达给大脑。