Bacterial recognition by PGRP-SA and downstream signalling by Toll/DIF sustain commensal gut bacteria in Drosophila

The gut sets the immune and metabolic parameters for the survival of commensal bacteria. We report that in Drosophila, deficiency in bacterial recognition upstream of Toll/NF-κB signalling resulted in reduced density and diversity of gut bacteria. Translational regulation factor 4E-BP, a transcriptional target of Toll/NF-κB, mediated this host-bacteriome interaction. In healthy flies, Toll activated 4E-BP, which enabled fat catabolism, which resulted in sustaining of the bacteriome. The presence of gut bacteria kept Toll signalling activity thus ensuring the feedback loop of their own preservation. When Toll activity was absent, TOR-mediated suppression of 4E-BP made fat resources inaccessible and this correlated with loss of intestinal bacterial density. This could be overcome by genetic or pharmacological inhibition of TOR, which restored bacterial density. Our results give insights into how an animal integrates immune sensing and metabolism to maintain indigenous bacteria in a healthy gut.Author summary: Gut bacteria (collectively called the bacteriome) have beneficial effects on the physiology of animals but how they are retained by the host is an open question. Here we report that the immune system of the fly recognises these bacteria and activates a metabolic pathway leading to the regulated breakdown of lipids. The latter seems to be important for retention of intestinal bacteria because when lipids stores accumulate, the number of intestinal bacteria that can be cultivated out of the fly gut is significantly reduced. In fly mutants with a reduced immune recognition or response, the TOR pathway, a major pathway for metabolism and growth, inhibits lipid breakdown and is responsible for increased fat accumulation in the gut. Blocking this pathway (pharmacologically or genetically) restores both lipid levels as well as the density of cultivable gut bacteria to normal levels. Our results show that this interplay between immunity and metabolism with the regulation of lipid catabolism at its centre is important for the retention of the intestinal bacteriome.