Control of gut colonization by the prominent gut bacterium Bacteroides thetaiotaomicron

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PROJECT SUMMARY Bacteroides thetaiotaomicron is a beneficial gut bacterium strongly associated with lean and healthy individuals. This proposal seeks to understand how colonization of the mammalian gut by B. thetaiotaomicron is promoted by atypical forms of three highly conserved proteins: a paralog of the essential translation factor EF-G, designated EF-G2; the essential transcription termination factor Rho (BtRho), which harbors a ~300-residue long domain absent from canonical Rho proteins and specifically required for gut colonization; and Roc, a transcriptional regulator silenced by the simple sugars glucose and fructose. First, we will identify the biochemical properties of EF-G2 that distinguish it from EF-G and render it necessary for gut colonization, and test the hypothesis that EF-G2 is an energy-saving translation factor because it lacks the guanosine triphosphate hydrolyzing activity in the presence of vacant ribosomes that characterizes EF-G. Second, we will investigate the signals, genes, and regions of the extra domain that determine liquid-liquid phase separation in BtRho and identify genes regulated by the extra domain of BtRho. And third, we will determine how simple sugars control Roc amounts via the 5' leader region of the roc mRNA and identify genes controlled by Roc when B. thetaiotaomicron is in the murine gut. The proposed research will reveal novel biochemical activities for widespread proteins and uncover novel colonization determinants. Moreover, it will directly advance the engineering of commensal bacteria with desirable properties.