Townsend, G. E.; Verma, K.; Kabonick, S. G.; Winokur, K. M.; Flanagan, J. M.; Groisman, E. A.

Glucose homeostasis is governed by peptidases across the kingdom of life. Host overconsumption of glucose transforms gut microbial compositions and activities. Here, we identify an IDE-like M16 peptidase in human gut commensal Bacteroides that controls glucose-dependent inhibition of the transcriptional regulator, Cur, which is important for intestinal colonization and host-microbial interactions. This regulatory paradigm is independent of fructose, establishing a specific pathway whereby glucose signaling hinders commensal fitness in the host. We determined that this peptidase cleaves targets of other M16-family peptidases, including insulin, to control carbon metabolism through the oxidative pentose phosphate pathway (OPPP). Furthermore, we show that peptidase activity governs the abundance of glycolytic enzymes to alter Cur activity. These findings establish that the activity of an M16 peptidase mediates changes to global transcription in Bacteroides species when glucose is abundant in the host diet.