Gut bacteria are essential to human health, but there is insufficient knowledge about the factors and mechanisms that make beneficial bacteria successful colonizers. One of the most common bacterial species in the human gut is Bacteroides thetaiotaomicron, which is common in lean, healthy people. Clinical trials are currently underway to treat numerous diseases by modifying the gut microbiota.

Researchers at Yale found a new mechanism for beneficial colonization of gut bacteria. Bacteroides thetaiotaomicron responded to carbon deficiency by sequestering part of the molecules for an essential transcription factor in a membrane-less compartment.

The team determined that sequestration of the transcription factor increased its activity, which altered the expression of hundreds of bacterial genes, including several that promote gut colonization and control central metabolic pathways in the bacteria. These findings reveal that “good” bacteria use the storage of molecules in membraneless compartments as an essential strategy to colonize the mammalian gut.

Aimilia Krypotou, a postdoctoral researcher in Groisman’s lab and lead author of the study from Yale University, said: “One of the things that came out is that when an organism is starved for carbon, that’s the signal that helps produce traits that are good for survival in the gut.”

Krypotou hypothesized that the different regions would impart a new biophysical feature to the transcription factor essential for bacteria to survive in the gut. She successfully tested the theory in a series of studies.

She said, “Most studies only look at an abundance of bacteria. If we don’t understand what’s happening at the molecular level, we don’t know if it would help.”

Groisman said, “Krypotou’s main insight was to derive new properties for the bacterial transcription factor – called Rho – based on the extra region. Sequestration of the transcription factor occurs through a process known as liquid-liquid phase separation, a ubiquitous phenomenon present in a wide variety of cells, including those of humans.”

Groisman said, “This phenomenon is well known, but it is usually associated with stress in eukaryotic organisms, such as plants, animals and fungi. Recently, it was realized that it can also happen to bacteria. In our case, we found that it occurs in commensal gut bacteria, which need it to survive in the gut. You might imagine that if you manipulated organisms that are susceptible to this effect, you might be able to improve organisms that are beneficial to humans.

He was able to predict new characteristics for the bacterial transcription factor Rho based on the different regions. The transcription factor is sequestered through a mechanism known as liquid-liquid phase separation, which is found in a wide variety of cells, including human cells.

This newly discovered mechanism by which ‘good’ bacteria colonize the gut could spur the development of new probiotic therapies for gut health.

By triggering the sequestration of Rho molecules in a membraneless compartment, carbon starvation and the murine gut increase the activity of Rho termination, altering the expression of numerous genes. The results also show how a single, acquired domain within a highly conserved protein expanded its properties without altering its core biochemical function and now plays a critical role in the organism’s physiology.

Magazine reference:

  1. Emilia Krypotou, Xiaohui Gao, et al. Bacteria require phase separation for fitness in the mammalian gut. Science. DOI: 10.1126/science.abn7229