Gut microbial metabolites link dietary history to appetite regulation.

All metazoan guts harbor commensal communities, from a dozen bacterial species in Drosophila to hundreds in humans. Here, we condition flies with diets containing varying levels of protein and sugar to investigate the impact of dietary history on the interaction between commensal gut bacteria and feeding adaptation in Drosophila. We find that appetite increases with dietary protein, dependent on total gut bacteria content, and enhanced by a drug that promotes the growth of short-chain fatty acid (SCFA)-producing gut bacteria. Lactiplantibacillus is a potential source of butyrate, while Acetobacter produces acetate. Mono-association with Acetobacter or Lactiplantibacillus increases food intake. Mutant strains unable to produce acetate or butyrate have lesser effects. Finally, adding acetate or butyrate to conditioning diets recapitulates the appetitive effect of Acetobacter and Lactiplantibacillus, respectively. Our findings suggest that protein-enriched diets enhance appetite by promoting the interaction between commensal bacteria and the host, with bacterial SCFAs as a conduit.