Gut microbial metabolites link dietary history to appetite regulation

All metazoan guts harbor commensal communities, from a dozen bacterial species in <i>Drosophila</i> 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 <i>Drosophila</i>. 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. <i>Lactiplantibacillus</i> is a potential source of butyrate, while <i>Acetobacter</i> produces acetate. Mono-association with <i>Acetobacter</i> or <i>Lactiplantibacillus</i> 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 <i>Acetobacter</i> and <i>Lactiplantibacillus</i>, 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.