Response of the microbiome–gut–brain axis in Drosophila to amino acid deficit

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 kwashiorkor 1 . 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. In Drosophila , an amino acid deficit triggers the expression of the neuropeptide CNMamide in gut enterocytes, which promotes a compensatory appetite for essential over non-essential amino acids, and this process is modulated by the microbiome.