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

Human dietary choices control the gut microbiome. Industrialized populations consume abundant amounts of glucose and fructose, resulting in microbe-dependent intestinal disorders. Simple sugars inhibit the carbohydrate utilization regulator (Cur), a transcription factor in members of the prominent gut bacterial phylum, Bacteroidetes. Cur controls 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 Bacteroides 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 cur is absent, indicating PPi is sufficient to drive glycolysis in these bacteria. Our findings reveal how sugar-rich diets inhibit Cur, thereby disrupting Bacteroides fitness and diminishing products that are beneficial to the host. In this study, Kabonick et. al. reveal how high sugar diets disrupt Bacteroides intestinal fitness via a glycolytic pathway that is hierarchically governed to rapidly alter transcription by controlling the global transcription factor, Cur, functionally mimicking carbon catabolite repression. The intimate connection between the catabolism of dietary sugars and dramatic alterations to the Bacteroides transcriptome coordinates the prioritization of intestinal nutrients, a process that is necessary for gut fitness.