From parental antibiotics to offspring locomotion: L-norvaline links microbiome disruption to intergenerational reprogramming in Drosophila

Abstract

The maternal microbiome during oogenesis is a critical but underappreciated regulator of offspring physiology. Using Drosophila melanogaster as a model, we show that a single, transient antibiotic exposure during oogenesis, without direct offspring exposure, is sufficient to reprogram larval behaviour, gene expression, and metabolism. Adult flies exposed to either ciprofloxacin or vancomycin produced third-instar larvae with significantly reduced crawling speed and a significantly higher prevalence of abnormal locomotion. Transcriptomic profiling revealed widespread downregulation of genes governing energy metabolism, particularly the tricarboxylic acid cycle, as well as cuticle development and protein folding. Metabolomic profiling identified elevation of L-norvaline across both antibiotic groups, and acute parental supplementation with L-norvaline alone recapitulated the observed crawling deficits, directly implicating this metabolite in the phenotype. These findings demonstrate that even brief disruption of the microbiome during oogenesis triggers a cascade of intergenerational physiological changes, establishing this window as a key period of microbiome-dependent offspring programming.