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NIH Research Matters

May 9, 2011

Survival Tactics of a Common Gut Microbe

In a recent mouse study, scientists discovered how a common gut bacterium sends a “do not attack” signal to the immune system. The finding helps explain how our bodies distinguish between harmful microbes and those essential for health.

Microscope image of microbes on intestine surface.

Microbes colonizing the surface of the mouse colon. Yellow cells are Escherichia coli; red cells are Bacteroides fragilis. Intestinal tissues are labeled in green with blue nuclei. Credit: S. Melanie Lee/Caltech.

Trillions of microbes thrive in our gut. They can help us digest our food, prevent infections, and may even affect our risk of developing autoimmune diseases. These helpful microbes remain relatively undisturbed by the human immune system. But small numbers of disease-causing microbes, like salmonella, elicit attacks from these same immune defenses. How the immune system knows which to attack and which to ignore—especially when friend and foe can look very similar—has been a long-standing mystery.

To investigate, a research team led by Dr. Sarkis K. Mazmanian of the California Institute of Technology studied a common friendly, or commensal, gut bacterium, Bacteroides fragilis, in the mouse gut. The study was funded in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID). The report appeared online on April 21, 2011, in Science.

To find out how B. fragilis avoids attack, the team studied germ-free mice whose guts were colonized with B. fragilis. The colonized mice did not show an increase in T helper 17 (Th17) cells—immune cells important for eliminating harmful pathogens.

In a previous study, Mazmanian had shown that the beneficial effect of B. fragilis requires a molecule named Polysaccharide A (PSA). When the researchers removed PSA from B. fragilis, they found that mouse Th17 cells responded.

Next, to determine how B. fragilis suppress Th17 cells, the researchers inactivated components of the animals’ immune response. Signaling through Toll-like receptors has been shown to both activate and restrain immune responses, and PSA is known to act through the mouse Toll-like receptor 2 (TLR2). When the researchers inactivated mouse TLR2, the number of Th17 cells increased, and the cells prevented intestinal colonization of B. fragilis. Similarly, cells called Treg cells normally suppress Th17 responses to prevent the immune system from attacking its own tissues. When the researchers inactivated mouse Treg cells, they also saw an increase in Th17 cells and a reduction in B. fragilis intestinal colonization.

Researchers had previously thought that commensal gut bacteria avoided immune detection by living far away from the surface of the intestine. Using a 3D microscopy technique, Mazmanian’s team found that B. fragilis occupies a unique niche within the mucosal lining of the mouse’s colon, in close contact with the immune system.

Taken together, the results suggest that B. fragilis evades the gut’s immune response by coercing the immune system into activating Treg cells. It does this by producing PSA, which is detected in the mouse intestine by TLR2.

“These bacteria live inside us for our entire lives, and they’ve evolved to look and act like us, as part of us,” says Mazmanian. “As far as our immune system is concerned, the molecules made by gut bacteria should be tolerated similarly to our own molecules. Except in this case, the bacteria 'teach' us to tolerate them, for both our benefit and theirs.”

—by Amy Alabaster

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Editor: Harrison Wein, Ph.D.
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NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

This page last reviewed on December 4, 2012

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