Research News

A new Cleveland Clinic study published in Cell Host & Microbe shows that HMGB1 prevents harmful bacterial adhesion to maintain gut health. The protein prevents bacteria from binding to cells in the intestine, reducing risk for digestive disease and infection.

Why does bacterial adhesion matter?

The trillions of bacteria that live in our gut are essential for digesting our food, regulating critical biological functions and protecting us from infection. Gut bacteria live at the outer edge of the mucus that covers the surface of the colon, not within colon tissue. These bacteria can invade into the mucus and attack the colon, but they rarely do so. When they do attach to the intestine, it causes infection or diseases like ulcerative colitis.

For a long time, people have thought that bacteria in the normal microbiome, called commensal bacteria, do not attack the intestine because they cooperate with their host by default. The Messer lab found that even commensal bacteria will stick to the colon and take its resources for themselves, but this behavior is both discouraged and prevented by HMGB1 in the colonic mucus.

“It’s a myth that ‘good’ bacteria never attach to our intestines and ‘bad’ bacteria always do,” says study lead author Jeanette Messer, DVM, PhD. “Even beneficial microbes can cause harm if they stick to intestinal cells. Our findings describe when and how these bacteria attach to our intestines.”

What is HMGB1?

HMGB1 (high mobility group box 1) is one of the most important proteins in our cells. It organizes our DNA so it can fit inside our cells and be read properly. Our immune systems use HMGB1 to amplify inflammation when tissue is damaged. The Messer Lab is the first to identify HMGB1’s role in controlling the gut microbiome and defending against bacterial damage.

What does HMGB1 do to prevent bacterial adhesion?

The Messer Lab found that HMGB1 binds to a specific amino acid sequence, called ToH1, in the machinery that bacteria use to stick to host tissues. The result is bacteria clump together, preventing movement through the mucus that protects our colons. HMGB1 even signals the microbes to turn off molecules they need for bacterial adhesion. The intestine calibrates the amount of HMGB1 in mucus based on signals it receives from gut bacteria.

“The bacteria in our microbiomes can’t want anything, but if they could, they would want to live in peace. They wouldn’t want to make us sick, because that would ruin their home,” Dr. Messer says. “This is a type of host-microbe feedback loop that lets that happen.”

How is HMGB1 connected to inflammatory bowel disease?

Through this study, the Messer Lab uncovered a link between HMGB1 and inflammatory bowel disease (IBD). A key feature of ulcerative colitis (UC) is that bacteria adhere to intestinal tissue, causing damage and inflammation. Colon tissue samples from individuals with UC showed that lower HMGB1 levels in mucus correlated with higher bacterial adhesion, and vice versa. Preclinical studies identified the ways HMGB1 failure leads tissue damage and disease seen in patients with UC. Many different “friendly” gut bacteria were found to use ToH1 adhesion to attack the colon. Those same bacteria were found to be kept in check by HMGB1.

“Because this vulnerability is across many bacteria, we can now investigate precision therapies that prevent the root case of a disease without disrupting the rest of the microbiome or promoting antibiotic resistance,” Dr. Messer says.