ABSTRACTDiscovered at the beginning of the 20thcentury by Nobel laureate Élie Metchnikoff, probiotics have more recently emerged as a potential noninvasive therapeutic approach for the treatment of various chronic diseases. However, recent population-based clinical studies suggest that probiotics are often ineffective and may even exhibit potential deleterious effects. Hence, a deeper molecular understanding of strain-specific beneficial effects, together with the identification of endogenous/exogenous factors modulating probiotic efficacy, is needed. The lack of consistency in probiotic efficacy, together with the observation that numerous preclinical findings on probiotics are not translating once applied to humans through clinical trials, suggests a central role for environmental factors, such as dietary patterns, in probiotic efficacy. Two recent studies have been instrumental in filling this knowledge gap, defining the role played by diet in probiotic efficacy on metabolic deregulations in both mouse models and humans .