How subtle bacterial shifts keep gut inflammation at bay

One of the most captivating mysteries about the immune system is how it manages to keep its healthy equilibrium—staying on high alert and ready to react to harmful invaders or damaged cells, while remaining calm in the presence of innocent triggers such as food.

When it comes to gut immunity, this delicate balance might hinge on a tiny molecule on the surface of gut bacteria, according to a new Harvard Medical School-led study.

The research, done in mice, reveals that a small structural tweak in lipid A—a fatty-sugar molecule that sits on the outer surface of many gut bacteria—can determine whether immune cells in the colon go on the offensive or remain in a state of peaceful vigilance.

The work, published in Cell, can inform new ways to prevent or treat inflammatory bowel diseases such as Crohn’s, including the design of microbiome-targeted therapies that enhance gut immunity.

In most disease-causing bacteria, lipid A usually comes in a form with six fatty acid chains, which triggers a strong inflammatory response. The HMS-led team discovered that a rare four-chain version found in many bacteria that live in the intestine instead triggers gut cells to release a chemical that calms the immune system and helps sustain protective regulatory T cells (Tregs).

“Our findings highlight how subtle differences in microbial molecules can dramatically alter immune responses,” said senior author Dennis Kasper, the HMS William Ellery Channing Professor of Medicine at Brigham and Women’s Hospital and professor of immunology in the Blavatnik Institute at HMS. “It’s not the mere presence of gut bacteria but the shape of their molecules that can alter immune behavior.”

A tiny molecular difference, a potent effect

The study found that the rarer four-fatty acid chain version of the molecule triggered the release of inflammation-calming interferon beta. The research also revealed that once this form of the molecule touches the surface of an immune cell, it activates an alarm bell—a receptor on the surface of immune cells called toll-like receptor 4 (TLR4).

In most cases, TLR4 summons other immune cells to prepare for attack. But in this case, it absorbs the bacterial lipid molecule and triggers the release of inflammation-calming interferon beta. Interferon beta, in turn, maintains the presence of immune-regulating Tregs that keep the brakes on aberrant immunity to ensure the immune system does not mistakenly launch an offensive against innocent bystanders such as food proteins or beneficial microbes.

When a group of mice with a form of colitis that mimics human inflammatory bowel disease were given the four-fatty-acid chain version of the molecule with their food, these animals’ colons were shielded from inflammation and fared much better than mice with colitis that did not get the molecule as part of their diet. The treated group had minimal signs of inflammation and their colons remained healthier. By contrast, the untreated animals developed severe colitis.

“These insights can help us think about new ways to modulate colon immunity via lab-made bacterial molecules as a way to target gut inflammation,” Kasper said.

A patent application has been filed by Harvard University based on the work reported in this manuscript.