Stimulating the survival of a beneficial bacteria in the human gut

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

The microbes that inhabit 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 could enable medical interventions that improve the gut and promote overall human health. In a new study, Yale researchers have discovered a new mechanism by which these bacteria colonize the gut.

Specifically, the Yale team found that one of the most abundant beneficial species found in the human gut showed an increase in colonization potential when experiencing carbon limitation – a finding that could lead to new clinical interventions to promote a healthy gut. to support. The findings were published on March 16 Science.

Based in the lab of geneticist Eduardo Groisman, the Waldemar Von Zedtwitz Professor of Microbial Pathogenesis, the Yale team found that the beneficial gut bacteria Bacteroides thetaiotaomicron responded to starvation for carbon – an important building block for all cells – by destroying some of the molecules for an essential transcription factor in a membraneless 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.

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

“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,” said Aimilia Krypotou, a postdoctoral researcher in Groisman’s lab and lead author of the study.

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

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

An awareness of these membraneless compartments actually goes back a hundred years, Groisman said. Krypotou’s main insight, he said, was deriving 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.

“This phenomenon is well known, but most commonly associated with stress in eukaryotic organisms, such as plants, animals and fungi,” Groisman said. “Recently it was realized that it can also happen to bacteria and in our case we found that it occurs in commensal gut bacteria, which need it to survive in the gut. You could imagine that if you manipulated organisms that are susceptible for this purpose one might perhaps improve organisms beneficial to man.”

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

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

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

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