Scientists monitor crosstalk between intestinal microbes and immune system.
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 the journal Cell, provide a blueprint for identifying important microbial influencers of disease and health and can help scientists develop precision–targeted treatments.

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 the work, Dennis Kasper’s microbiology team collaborated with immunologists from the HMS lab run by Diane Mathis and Christophe Benoist.

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.

When researchers analyzed bacterial effects on genes that regulate the activity of cytokines – signaling molecules responsible for inducing inflammation in response to infection, cancer and other diseases – they once again observed the same balancing dynamic at play: Some bacteria boosted the activity of these genes while others turned it down.

Also, contrary to expectations, the researchers said, bacteria that belonged to the same class did not necessarily have the same, or even similar, effects on immune cells. That observation, researchers say, suggests an evolutionary fail–safe mechanism to ensure the preservation of key immune functions even if whole classes of bacteria are lost.

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.