The microbes that inhabit the gut are critical to human health, and understanding the factors that promote the growth of beneficial bacterial species—known as “good” bacteria—in the gut may enable medical interventions that promote gut and overall health . In a new study, Yale researchers have revealed a new mechanism by which these bacteria colonize the gut.
Specifically, the Yale team discovered that one of the most abundant beneficial species found in the human gut showed an increase in colonization potential when it experienced carbon limitation—a finding that could inform new clinical interventions to support a healthy gut . The results were published on 16 March i Science.
The Yale team, based in the laboratory of geneticist Eduardo Groisman, Waldemar Von Zedtwitz Professor of Microbial Pathogenesis, found that the beneficial gut bacterium Bacteroides thetaiotaomicron responded to starvation for carbon—a major building block of all cells—by sequestering some of molecules for an essential transcription factor in a membraneless compartment.
The team found that sequestering the transcription factor increased its activity, which modified the expression of hundreds of bacterial genes, including several that promote intestinal colonization and control key metabolic pathways in the bacterium. These results reveal that “good” bacteria use the sequestration of molecules in membrane-less spaces as a vital strategy to colonize the mammalian gut.
Bacteroides thetaiotaomicron and other bacteria found 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, induces the production of colonization factors in beneficial gut bacteria, the researchers found.
“One of the things that emerged 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 postdoc in Groisman’s lab and lead author of the study.
A confluence of observations from the lab’s previous research 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 the size of 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 absent from homologous proteins.
Krypotou then hypothesized that the extra region might impart a new biophysical property to the transcription factor required for the bacteria to survive in the gut, and successfully conducted a series of experiments to test the hypothesis.
An awareness of these membraneless spaces actually goes back a hundred years, Groisman said. Krypotou’s key insight, he said, was to derive new properties of the bacterial transcription factor — called Rho — based on the extra region. Sequestration of the transcription factor occurs by a process known as liquid-liquid phase separation, a ubiquitous phenomenon present in a wide variety of cells, including those of humans.
“This phenomenon has been known but is usually associated with stress in eukaryotic organisms such as plants, animals and fungi,” Groisman said. “Recently it was realized that it can also happen with bacteria, and in our case we found that it occurs in commensal gut bacteria that require it to survive in the gut. You could think, potentially, that if you were to By manipulating organisms prone to this effect, one might be able to improve organisms that are beneficial to humans.”
The findings could help spur the development of new probiotic therapies for gut health, Krypotou said.
“Most studies just 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.”
Emilia Krypotou et al., Bacteria require phase separation for fitness in the mammalian gut, Science (2023). DOI: 10.1126/science.abn7229