The
human gut is home to some 100 trillion bacteria, comprising between 250 and 500
species. This astounding array of organisms, collectively known as the gut
microbiome, is a powerful regulator of disease and health and has been
implicated in conditions ranging from inflammatory bowel disease to multiple sclerosis.
Gut
microbes engage in an intricately choreographed conversation with the immune
system, stimulating it just enough to keep disease-causing invaders at bay,
while at the same time reining it in so it doesn't mistakenly launch an attack
on the body.
So
far, scientists have been able to listen to bits and pieces of the conversation
between bacteria and individual immune cells or a handful of genes.
Now,
for the first time, scientists from Harvard Medical School have managed to
"listen in" on the crosstalk between individual microbes and the
entire cast of immune cells and genes expressed in the gut.
The
experiments, published Feb. 16 in Cell, provide a blueprint for identifying
important microbial influencers of disease and health and can help scientists
develop precision-targeted treatments.
Past
research has looked at links between disease and the presence or absence of
certain classes of bacteria in the gut. By contrast, the HMS team homed in on
one microbe at a time and its effects on nearly all immune cells and intestinal
genes, an approach that offers a more precise understanding of the interplay
between individual gut microbes and their hosts. Beyond that, the team said,
the approach could help scientists screen for molecules or bacterial strains
that can be used therapeutically to fine-tune certain immune responses.
For
their experiments, the team collected 53 common bacterial species from human
guts and seeded them in sterile mouse guts, one microbe at a time. Two weeks
later, the scientists performed immune and genomic analyses, comparing the
results with those of mice whose guts were completely microbe-free. Scientists
assessed each microbe's effects on 21 types of immune cells and on the activity
of the entire cast of genes that regulate intestinal immunity.
Each
immune cell type was affected by bacteria in a range of ways, the team
observed. Some bacteria exerted a powerful influence, while others had far more
subtle effects. Very few microbes produced no effect at all.
Some
bacteria boosted the activity of certain cells, while others dampened the
activity of the very same cells. These oppositional effects, the researchers
say, suggest an evolutionary checks-and-balances mechanism to ensure that no
single bacterium can overpower the others in its effects on the immune system.
Similarly, some bacteria upregulated certain genes, while others downregulated
them, indicating that microbes can have balancing effects on intestinal gene
expression.
A
quarter of the 53 bacteria studied potently boosted the numbers of immune cells
known as regulatory T cells, which are responsible for taming inflammation and
maintaining immune self-tolerance to shield the body from self-inflicted immune
assault. Another interesting observation, the researchers said, was that a
single, little-known microbe, Fusobacterium varium, had, overall, the most
powerful effect on immune cells across the board. These effects included
suppression of naturally secreted antimicrobials and the ability to turn on several
genes that promote inflammation.
The
most potently affected class of immune cells was plasmacytoid dendritic cells,
known to affect the function of regulatory T-cells and the secretion of
interferons, naturally occurring proteins that fend off viruses. Thirty-eight
percent of microbes boosted the levels of these dendritic cells, while 8
percent lowered their levels.
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Posted by Dr. Tim Sandle
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