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

Seth G. Kabonick, Kamalesh Verma, Jennifer L. Modesto, Victoria H. Pearce, Kailyn M. Winokur, Eduardo A. Groisman and Guy E. Townsend ()
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Seth G. Kabonick: Penn State College of Medicine
Kamalesh Verma: Penn State College of Medicine
Jennifer L. Modesto: Penn State College of Medicine
Victoria H. Pearce: Penn State College of Medicine
Kailyn M. Winokur: Penn State College of Medicine
Eduardo A. Groisman: Yale University School of Medicine
Guy E. Townsend: Penn State College of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59704-3

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