Despite effective weight-reduction strategies, individuals fail to maintain the reduced weight. The mechanisms that underlie the weight-cycling-induced phenomena and the influence of the gut microbiota are not well understood. Thaiss et al. used mouse models of weight loss and recurrent obesity and found that obesity-induced alterations to the microbiome persist over long periods of time and enhance the rate of weight gain during secondary metabolic challenge. In addition, low flavonoid levels in post-dieting mice were shown to contribute to the increased weight regain, whereas their therapeutic replenishment ameliorated this susceptibility. The authors propose a model whereby a high-fat diet promotes the growth of flavonoid-metabolizing bacteria, which, in turn, decrease the amount of bioavailable flavonoids, thereby negatively regulating energy expenditure and promoting exaggerated recurrent weight gain.