The gut microbiome protects against pathogen colonization, but in cirrhosis this community often becomes dysbiotic, predisposing patients to systemic infections. We recently showed that lactulose, a non-absorbable carbohydrate widely prescribed in cirrhosis, promotes Escherichia coli evolution by selecting for constitutive lac operon mutants with enhanced colonization capacity. Here, we investigated whether dietary carbohydrates could modulate these effects. Using in vitro growth assays, whole-genome sequencing, and murine models, we found that raffinose - imported by the same transporter as lactulose - suppresses the emergence of lac operon mutants and limits E. coli proliferation. This effect was dose-dependent, and in mice, raffinose blocked the enhanced colonization normally induced by lactulose. Unexpectedly, sequential exposure to lactulose followed by raffinose selected for secondary mutations that conferred the ability to metabolize raffinose, representing a novel “two-hit” adaptive mechanism. These findings reveal how diet composition and order of exposure can redirect microbial evolution, and highlight the potential of precision dietary interventions to mitigate lactulose-associated pathogenic adaptations in cirrhosis.