EMBO: Most of the genes in the human body do not come from human cells but are
found within the trillions of microbes that live on or within the human
body, particularly in the gut. Working out the functions of these
microbial genes is a big challenge because many of the microbes that
live within us are extremely reluctant to grow when cultured under
laboratory conditions.
Researchers at Harvard Medical School and Columbia University in the
United States have developed a way to study the functions of
hard-to-grow bacteria that contribute to the composition of the gut
microbiome. The new method is published in the journal Molecular Systems
Biology.
"Our method, TFUMseq, is a powerful tool for understanding how the
wealth of microbes that we harbour in our bodies are so successful at
colonizing us. It provides a general high-throughput approach to
identify genes that enhance the fitness of microbes over time as they
grow in complex living organisms," says Georg Gerber, one of the lead
authors on the study, and Assistant Professor at Brigham and Women's
Hospital at Harvard Medical School.
The new method circumvents the problem of not being able to culture
many of these bacteria in the lab by transferring genes from these
bacteria into another bacterial species that is easier to work with. It
is then possible to look for tell-tale signs of advantages conferred to
the recipient bacterial species as it grows in the mammalian gut over
time.
In their demonstration, the researchers used the bacterium
Bacteroides thetaiotaomicron, a microbe that lives in the human
intestinal tract, as their "donor organism," that is the one whose
functions they wanted to study in more detail. The more manageable
recipient was Escherichia coli, which can be easily manipulated in the
lab. E. coli organisms harbouring fragments of DNA from the "donor
organism" were then fed to germ-free mice, which are animals that are
raised in special environments (isolators) that prevent the entry of any
bacteria.
The scientists were able to use the method to uncover
improvements in the capabilities or fitness of the recipient E. coli
bacteria growing in the mouse gut that were due to characteristics being
passed on from the source bacterium. In particular, they detected E.
coli organisms that were being selected due to their improved abilities
to use different carbohydrates as a source of energy, a property
conferred by the source bacterium B. thetaiotaomicron.
The work is the first time that a large-scale functional genomic
approach has been used to systematically examine how bacteria can gain
capabilities that improve their ability to colonize living organisms, in
this case mice. The work also allows building up a picture of the
behavior of different genes of the gut bacteria over time, so-called
kinetic information. This information provides clues as to when
different genes are most important during the complex process of
colonizing a living organism.
Harris Wang, a lead author on the study, and Assistant Professor at
Columbia University, added: "The use of the TFUMseq approach could allow
the rational design of bacterial strains for various clinical
applications, for example improving the ability of probiotic bacteria to
colonize the gut, resisting colonization by pathogens, compensating for
unbalanced diets, such as too much fat or sugar, or improving the
function of the immune system to prevent diseases."
Improving microbial fitness in the mammalian gut by in vivo temporal functional metagenomics
Stephanie J. Yaung, Luxue Deng, Ning Li, Jonathan L. Braff, George M. Church, Lynn Bry, Harris H. Wang and Georg K. Gerber
Read the paper:
http://msb.embopress.org/content/11/3/788