The human gut is home to some 100 trillion bacteria, comprising between 250 and 500 species. Known as the gut microbiome, this microbial collective 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 intricate conversation with the immune system, stimulating it just enough to keep disease-causing invaders at bay, while at the same time checking it so it doesn’t mistakenly attack the body. So far, scientists have been able to pick up only bits and pieces of that conversation.
Now, scientists from HMS have managed to “listen” to the crosstalk between individual microbes and the immune cells and genes expressed in the gut. They did this by focusing on one microbe at a time and deciphering its effects on nearly all immune cells and intestinal genes, an approach that yielded a more precise understanding of the interplay between individual gut microbes and their hosts.
The experiments, published February 23 in Cell, provide a blueprint for identifying microbial influencers of disease and health, one that can help scientists screen for molecules or bacterial strains that can be used therapeutically to fine-tune certain immune responses.
“We set out to map interactions between bacteria and the immune system,” says senior investigator Dennis Kasper, an HMS professor of medicine and microbiology and immunobiology, “and hoped that could eventually lead to the development of an apothecary of agents tailored to modulate the immune system selectively and precisely.”
For the work, Kasper’s microbiology team collaborated with HMS immunologists Diane Mathis and Christophe Benoist.
“This research took place at the intersection of microbiology, immunology, and genetics,” says Mathis, an HMS professor of microbiology and immunobiology. “It illustrates the complex and synergistic ways in which multiple organs and organ systems operate in the body.”
Says Benoist, an HMS professor of microbiology and immunobiology, “Because we observed microbial effects mainly in the gut, we think that a microbe-based therapy would avoid the collateral damage seen with drugs that wipe out classes of the body’s immune cells.”
Modulating the gut immune system, Benoist adds, may also have broader beneficial effects because gut immunity has been linked to several autoimmune diseases, including rheumatoid arthritis, Crohn’s disease, and diabetes.
For the experiments, the team collected fifty-three 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 from mice whose guts were completely microbe-free. Scientists assessed each microbe’s effects on twenty-one types of immune cells and on the activity of all the genes that regulate intestinal immunity.
Each immune cell type was affected by bacteria in a range of ways. 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 help balance intestinal gene expression.
A quarter of the fifty-three bacteria studied boosted the census of regulatory T cells, which are responsible for taming inflammation and which help shield the body from self-inflicted immune assault.
The researchers also note that a single little-known microbe, Fusobacterium varium, had the most powerful effect on immune cells, including the suppression of naturally secreted antimicrobials and the ability to turn on several genes that promote inflammation.
The class of immune cells most affected 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 them.
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