Increasing the survival of a beneficial bacterium in the human gut

Phase separation of the transcription termination factor Rho in the commensal bacterium B. thetaiotaomicron controls gene expression and promotes bacterial fitness in the mammalian gut. Credit: Science (2023). DOI: 10.1126/science.abn7229

The microbes that live in the gut are critical to human health, and understanding the factors that encourage the growth of beneficial bacterial species – known as “good” bacteria – in the gut may enable medical interventions that promote gut health and overall human health. In a new study, Yale researchers have uncovered a novel mechanism by which these bacteria colonize the gut.

Specifically, the Yale team discovered that one of the most abundant beneficial species in the human gut showed increased colonization potential when carbon limitation occurs – a finding that could lead to novel clinical interventions to support a healthy gut. The results were published on March 16th Science.

The Yale team, based in the lab of geneticist Eduardo Groisman, the Waldemar von Zedtwitz Professor of Microbial Pathogenesis, found that the beneficial gut bacterium Bacteroides thetaiotaomicron responded to the lack of carbon — a major building block for all cells , by secreting part of it molecules for an essential transcription factor within a membraneless compartment.

The team found that sequestering the transcription factor increased its activity, altering the expression of hundreds of bacterial genes, including several that promote gut colonization and control key metabolic pathways in the bacterium. These results demonstrate that “good” bacteria use sequestration of molecules into membraneless compartments as an important strategy to colonize the mammalian gut.

Bacteroides thetaiotaomicron and other mammalian gut bacteria have access to nutrients ingested by the host animal. However, there are also longer periods in which the host organism does not eat. The lack of nutrients, including carbon, triggers the production of colonization factors in beneficial gut bacteria, the researchers found.

“One of the things that turned out is that a carbon-starved organism is the signal that helps produce traits that are good for gut survival,” said Aimilia Krypotou, a postdoctoral researcher in Groisman’s lab and lead author of the Learn.

A confluence of observations from previous research at the lab led to the breakthrough. The first was when Groisman noticed that the size of the transcription factor from the gut microbe was much larger than other well-studied homologous proteins from other bacterial species. The team then found that bacteria could not survive in the gut of a mouse without the extra region missing in homologous proteins.

Krypotou then hypothesized that the additional region might confer a new biophysical property on the transcription factor required for the bacteria to survive in the gut, and successfully conducted a series of experiments to test the hypothesis.

Awareness of these membraneless compartments actually goes back a hundred years, Groisman said. Krypotou’s key finding, he said, was deriving novel properties for the bacterial transcription factor – called Rho – based on the extra region. Transcription factor sequestration occurs through a process known as liquid-liquid phase separation, a ubiquitous phenomenon present in a wide variety of cells, including those of humans.

“This phenomenon is well known but is usually associated with stress in eukaryotic organisms such as plants, animals and fungi,” Groisman said. “Recently it was found that it can also happen in bacteria, and in our case we found that it occurs in commensal gut bacteria, which need it to survive in the gut, for that purpose maybe one could improve organisms useful to humans.” .”

The findings could help advance the development of new probiotic therapies for gut health, Krypotou said.

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

More information:
Emilia Krypotou et al, Bacteria require phase separation for fitness in the mammalian gut, Science (2023). DOI: 10.1126/science.abn7229

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