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

• Published in: Nature (London) Vol. 593; no. 7860; pp. 570 - 574
• Main Authors: Kim, Boram, Kanai, Makoto I., Oh, Yangkyun, Kyung, Minsoo, Kim, Eun-Kyoung, Jang, In-Hwan, Lee, Ji-Hoon, Kim, Sang-Gyu, Suh, Greg S. B., Lee, Won-Jae
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-05-2021; Nature Publishing Group
• Subjects: 14/19; 631/378/1488; 631/443/319; 64/24; 82/51; Amino acids; Amino Acids, Essential - administration & dosage; Amino Acids, Essential - deficiency; Animal Nutritional Physiological Phenomena; Animals; Animals, Genetically Modified; Appetite; Brain; Brain-Gut Axis; Carbohydrates; Deprivation; Diet; Drosophila; Drosophila - physiology; Enterocytes; Female; Females; Flies; Food; Food Preferences; Food selection; Food sources; Fruit flies; Gastrointestinal Microbiome; Germ-Free Life; Glucose; Gnotobiotic; Humanities and Social Sciences; Hunger; Hypotheses; Insects; Kinases; Leucine; Microbiomes; Microbiota (Symbiotic organisms); Midgut; multidisciplinary; Phosphorylation; Physiological aspects; Proteins; Receptors; Science; Science (multidisciplinary); Symbiosis; Taste receptors; Transcription factors; South Korea
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03522-2

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.