||Dr. David Relman
The notion that we are not alone began some 350 years ago, when
Leeuwenhoek trained his microscope on such samples as human hair
and teeth. He found in dental plaque a variety of tiny motile creatures,
noting that the little "animalcules" withered and died on contact
with hot coffee.
Subsequent centuries of scientific inquiry discovered the world
of bacteria, entrée to which was possible chiefly by cell culturing
techniques — literally getting the bugs to multiply on a
bed of food. That approach has limits though. What if the microbes
in a given environment don't like what you've given them to eat?
The problem with taking roll by cell culture is that you may be
serving steak to an audience of vegans, and would therefore not
know how many were at the table simply by counting cleaned plates.
Today, the tools for discovering what kind of microbial baggage
we carry are far more sophisticated and sensitive — measuring
ribosomal DNA (rDNA), for example — and the roles our fellow
travelers play are only starting to be understood.
Relman and his colleagues want to know the purpose of our internal
gardens, and their role in health and disease.
The conventional wisdom is that we begin life "sterile" (that
is, culture-negative, although there could be flora we don't yet
know about) until the rupture of the amniotic membranes. There
follows a long roster of benefits conferred by microbes throughout
human development, including vitamin production, food degradation
and colonization resistance. Microbial flora promote the terminal
differentiation of mucosa, the innate immune defenses and epithelial
homeostasis in the gut.
Recently, in what Relman termed "a truly surprising and revolutionary" role
for microbes, they appear to regulate fat storage. A recent article
in the Proceedings of the National Academy of Sciences showed
that "germ-free animals have significantly lower body fat than
those raised in a microbial-infected environment," Relman said. "That's
a result not previously suspected."
|Relman and his colleagues want
to know the purpose
of our internal gardens, and their role in health and
Because technology now permits a far broader view of microbes
than did cell culture, scientists can investigate the microbial
universe in more detail. Although there remain limits to detectability,
there seem to be about 80 phyla in nature, based on current estimates.
Focusing on bacteria that colonize the mouth, investigators have
discovered a wide diversity of microbes that belong primarily to
four phyla — the firmicutes, bacteroidetes, fusobacteria
and proteobacteria. Yet if you could follow a bite of dinner past
the mouth into the esophagus, stomach, small intestines, colon
and beyond, you would encounter distinct microbial neighborhoods
with very different characteristics. "The biota of the stomach
is distinct from the colon, or esophagus, or mouth," Relman said.
In the large intestine, for example, at least seven phyla are
represented. In one study, a look at three individuals found close
to 500 bacterial phylotypes in the colon and feces, 62 percent
of which were novel and 80 percent of which could not be cultivated.
When these scientists estimated the completeness of this survey,
they were humbled to find that their analysis of nearly 12,000
bacterial sequences had revealed no more than two-thirds of the
strains and species that were predicted to be present.
"Individuals vary quite distinctly in the make-up of their flora," Relman
said. "To answer the question, 'Who's there?' would require a very
large study population."
Beyond the fascination of what's aboard the human raft, Relman
and associates want to know the sources of variability in human
microbial colonization, and what factors perturb them. Clearly,
host genetics, diet and age play roles, but "there are not enough
data to know what's truly important, and to what degree."
As if it isn't hard enough to tease out the role of dominant microbial
species, the part "rare members" may play is even more of a mystery.
Relman suggested there may be "keystone" or "founder" species without
which the entire microbial ecosystem collapses.
A range of diseases known to have microbial elements is under
review in Relman's laboratory, including Crohn's disease, irritable
bowel syndrome, periodontitis, diarrhea, and even premature labor
and delivery. All are tied to disturbances in microbial ecology.
Thus far, periodontitis, a disease affecting about 40 percent of
the adult population in the U.S., is linked in a subset of patients
to an abundance of archaeal sequences during stages of severe disease.
To gain a better perspective on this largely hidden frontier,
Relman suggested harnessing microarray technology to do more high-throughput
analyses of microbial community structure, continue with rDNA screening,
establish correlations with host genotypes and develop more sophisticated
He called for a "second Human Genome Project" that would survey
the genomes of the organisms that populate our bodies. "We need
to ask, 'Who's there?', 'What are their genes?', 'What are their
functional capabilities? 'How do their patterns of gene expression
and associated activities define health?'"
One of his collaborations, with the Institute for Genomic Research
in Rockville, involves the "metagenomics" of both the human fecal
and oral microbiomes. He concluded, "The diversity and variation
of the human indigenous microbial flora is still poorly understood."
Relman's lecture is archived at www.videocast.nih.gov.