The common commensal gut bacterium Bacteroides thetaiotaomicron uses phase separation of the transcription termination factor Rho to colonize and thrive in the mammalian gut, according to a new study in mice. The findings suggest that phase separation may also be vital for other important gut microbes and relevant for novel microbiome-based clinical applications.

The gut microbiota plays a critical role in human health. Manipulating gut commensal communities could provide promising therapeutic pathways for treating a host of diseases. However, this goal requires understanding mechanisms that enable beneficial bacteria to colonize the gut – a complex process that includes successful competition for scarce nutrients and resistance to the host’s immune system.

Here, the researchers evaluated these mechanisms in B. thetaiotaomicron, one of the most abundant bacterial species in the human gut of healthy individuals and a species currently being tested in clinical trials as a potential therapeutic for gastrointestinal disorders.

The authors focused on the highly conserved transcription termination factor Rho, which is essential in regulating gene transcription in bacteria. However, unlike other bacteria, B. thetaiotaomicron’s Rho protein harbors a large intrinsically disordered domain (IDR).

The authors now show that the unique IDR of this Rho protein enables liquid-liquid phase separation of the transcription termination factor and is critical for B. thetaiotaomicron gene regulation in the gut.

Through in vitro and in vivo experiments in a mouse model, the authors found that B. thetaiotaomicron responded to the mammalian gut environment by sequestering Rho molecules within a membraneless compartment via phase separation. This IDR-dependent molecular condensation increased Rho termination activity, resulting in the modified transcription of hundreds of genes, including several required for gut fitness and colonization.

https://www.science.org/doi/10.1126/science.abn7229