Life Science Technologies
763 SCIENCE sciencecareers.org
Produced by the Science/AAAS Custom Publishing Office
how the gut microbiome of pigs is altered by antibiotics—a key
medical issue that can allow opportunistic infections such as
Clostridium difficile to take hold—she hooked up with CosmosID.
The collaborators took a metagenomics approach, shotgun sequencing all the DNA from Connelly’s pig fecal samples. The result
was a list predicting the bacterial species in the community and
their relative abundance, as well as the antibiotic genes likely present in the community as a whole. CosmosID is able to provide this
information (e.g., species and strains in a microbial community) to
customers due to its carefully curated database of standard microbial genomes, says Hasan.
From the CosmosID data, Connelly and colleagues determined not
only how antibiotics change the distribution of bacteria in the pig
gut, but also observed the community profile of antibiotic resistance.
From that, they could tell how treatment with the antibiotic ceftriax-one allowed organisms that seemed resistant to a variety of drugs to
move in, says Connelly.
The pig research helped propel one of Synthetic Biologics’ lead
products, ribaxamase, an oral medication the company hopes will
protect the gut microbiome from the effects of certain intravenous
antibiotics that can decimate healthy, beneficial populations and
open the door to nastier microorganisms. The drug stays in the gastrointestinal tract, degrading any intravenous antibiotics that reach
the gut, but does not penetrate the rest of the body, where those
antibiotics are working properly. In human trials, ribaxamase has already been found to reduce C. difficile infections.
Like Synthetic Biologics, Second Genome aims to turn microbial
genomes into ideas for medications, says Mohan Iyer, its chief business officer. For example, Second Genome compared microbes and
their functions, analyzing gastrointestinal biopsies of patients with
aggravated ulcerative colitis, those with well-controlled colitis, and
Through both genome and transcriptome sequencing, the researchers figured out which microbes were present, and which genes were
expressed, in healthy versus inflamed guts. From there, they worked
out which molecules made by the bacteria may promote or block
inflammation. A medication developed by Second Genome to calm
inflammation is now in phase 1 human trials.
Fish tacos, anyone?
Companies like Second Genome Solutions, CosmosID, and Diversigen can perform everything from sample prep and sequencing
to bioinformatics analysis, enabling scientists to plumb microbiome
genomes even if they lack the necessary expertise. But researchers
with the right know-how and interest have developed their own novel
tools and shared them with the community as well.
The catch is that most analytical tools ask one of two questions:
“Who’s in the sample?” or, “What genes does the community contain
as a group?” Each is only half the story, and it hasn’t been easy to
integrate these two datasets together, says Elhanan Borenstein, a
computational biologist at the University of Washington in Seattle.
The issue is that different taxonomic groups perform the same function in different peoples’ microbiomes. His laboratory recently came
up with a solution, a computational method called “Functional Shifts’
Taxonomic Contributors” (or Fish Taco for short).
For starters, the method surveys all the taxonomic groups in a
microbial sample, and based on what’s already known about their
genomes, infers which genes from the metagenomics sequencing go
with which organisms. It can also infer which genes belong with which
species when the individual organisms’ genomes are unavailable.
Then, it uses that information to help scientists determine which
species, or groups of species, are responsible for the crucial differences between the metagenomes of microbiomes they’re comparing.
For example, Borenstein and colleagues contrasted sequence data
from the gut microbiomes of people with type 2 diabetes and healthy
people. The metagenomics data showed an overabundance of several
sugar transporter genes in the diabetes samples, but which bacteria
were responsible for that extra sugar processing? FishTaco determined that members of the genus Escherichia were responsible for
one type of sugar transport, and members of Bifidobacterium contributed a different type.
This kind of information could help scientists envision how to
improve health by rebalancing the species that perform desired functions, says Borenstein, for example via antibiotic or probiotic treatments. “It opens the door to a much more tailored and personalized
approach for intervention,” he says.
It’s currently rare for microbial scientists to do this sort of integrated analysis, though they often make educated guesses as to which
bacteria perform which functions in a community, says Emily Hollister, a microbial ecologist at the Baylor College of Medicine and Texas
Children’s Microbiome Center at Texas Children’s Hospital in Houston.
She is applying Fish Taco to her own studies of microbial imbalance in
the gut and respiratory tract.
“The differences we identify may provide insight into potential
diagnostic or therapeutic targets,” says Hollister.
Baylor College of Medicine
Imperial College London
Oxford Nanopore Technologies
Second Genome Solutions
Texas Children’s Microbiome
University of California, Davis
University of Leuven
University of Washington
Amber Dance is a freelance writer living in Los Angeles.