Host genetic determinants of microbiota-dependent nutrition revealed by genome-wide analysis of Drosophila melanogaster

TLDR

Gut microbiota profoundly influences animal nutrition, yet the host genetic basis of this effect remains unknown and is likely conserved across species. This study uses Drosophila to show that host genotype modulates the microbiota’s impact on nutrition and to identify the genetic determinants of this variation. Key genes from the GWA study were validated by loss‑of‑function mutations that altered microbiota‑dependent nutritional outcomes. We found extensive genotype‑dependent microbiota effects on weight, protein, lipid, glucose, and glycogen, with GWA revealing distinct polymorphisms in conserved signalling genes, indicating that the microbiota interacts with multiple regulatory network nodes to shape nutrition.

Abstract

Animals bear communities of gut microorganisms with substantial effects on animal nutrition, but the host genetic basis of these effects is unknown. Here we use Drosophila to demonstrate substantial among-genotype variation in the effects of eliminating the gut microbiota on five host nutritional indices (weight, protein, lipid, glucose and glycogen contents); this includes variation in both the magnitude and direction of microbiota-dependent effects. Genome-wide association studies to identify the genetic basis of the microbiota-dependent variation reveal polymorphisms in largely non-overlapping sets of genes associated with variation in the nutritional traits, including strong representation of conserved genes functioning in signalling. Key genes identified by the GWA study are validated by loss-of-function mutations that altered microbiota-dependent nutritional effects. We conclude that the microbiota interacts with the animal at multiple points in the signalling and regulatory networks that determine animal nutrition. These interactions with the microbiota are probably conserved across animals, including humans. The gut microbiota affects animal nutrition, but it is unclear whether this effect depends on host genetic makeup. This study shows that host genotype modifies the gut microbiota's impact on host nutrition, and identifies genetic determinants of this variation in the fruit fly.