Hierarchical glycolytic pathways control the carbohydrate utilization regulator in human gut .

Human dietary choices control the gut microbiome. Industrialized populations consume abundant glucose and fructose, resulting in microbe-dependent intestinal disorders. Simple sugars inhibit the carbohydrate utilization regulator (Cur), a transcription factor in the prominent gut bacterial phylum, . Cur encodes products necessary for carbohydrate utilization, host immunomodulation, and intestinal colonization. Here, we demonstrate how simple sugars decrease Cur activity in the mammalian gut. Our findings in two species show that ATP-dependent fructose-1,6-bisphosphate (FBP) synthesis is necessary for glucose or fructose to inhibit Cur, but dispensable for growth because of an essential pyrophosphate (PPi)-dependent enzyme. Furthermore, we show that ATP-dependent FBP synthesis is required to regulate Cur in the gut but does not contribute to fitness when is absent, indicating PPi is sufficient to drive glycolysis in these bacteria. Our findings reveal how sugar-rich diets inhibit Cur, thereby disrupting fitness and diminishing products that are beneficial to the host.