A mitochondrial sirtuin shapes the intestinal microbiota by controlling lysozyme expression

Sirtuins are sensors that orchestrate cellular responses to adapt to changing situations. Here, we show that a protein-restricted diet induces strongly induces increased intestinal expression of the sole Drosophila mitochondrial sirtuin, dSirt4. To elucidate the effects of deregulated dSirt4 expression in the intestine, we analyzed dSirt4-deficient animals. These dSirt4-deficient flies show substantial changes in their intestine's intestinal proteome and their physiological properties. One of the most striking effects was the strong induction of lysozyme gene expression in the intestine, which was also matched by increased lysozyme activity. This effect was organ-autonomous, as it was also observed in flies in which dSirt4 was knocked down only in the intestinal enterocytes. This significantly increased lysozyme expression in response to dSirt4 downregulation did not reduce the total number of bacteria in the gut, but rather shifted the composition of the microbiota by reducing the number of gram-positive bacteria. This effect on microbiota composition can be attributed to dSirt4-dependent lysozyme expression, as it is absent in a lysozyme-deficient background. dSirt4 deficiency in the enterocytes shortened the lifespan of the flies, which was also observed in flies with ectopic lysozyme overexpression in the enterocytes. We assume that high lysozyme expression leads to a dysbiotic state of the microbiota associated with a shortened lifespan.