A mitochondrial sirtuin shapes the intestinal microbiota by controlling lysozyme expression

Sirtuins act as cellular sensors in the gut that control a substantial change in gut properties in response to environmental changes. Here we show that the only mitochondrial sirtuin of Drosophila, dSirt4 , is strongly up-regulated by a protein-reduced diet. Flies with a dSirt4 defect show strong changes in the protein pattern and physiological properties of their intestine. One of the most notable effects was the strong induction of lysozyme gene expression in the intestine, which also translates into enhanced lysozyme activity. This effect was cell autonomous, as it was also observed in flies with dsirt4 was exclusively silenced in enterocytes of the intestine. Although this strongly increased lysozyme expression, it did not reduce total bacterial load in the intestine, but rather changed the composition of the microbiota by reducing the number of gram-positive bacteria. This effect on microbiota composition can be attributed to the dSirt4-dependent lysozyme expression, as it was absent in a lysozyme-deficient background. dSirt4 deficiency in enterocytes reduced lifespan of flies, which was also observed in those flies experiencing ectopic lysozyme overexpression in enterocytes. This implies that strong lysozyme expression leads to a dysbiotic state associated with reduced lifespan.