Some Crohn’s genes make cells deaf to messages from good gut bacteria

Good gut bacteria might not help people with Crohn’s disease.

Protective microbial messages go unread in mice and in human immune cells with certain defective genes, researchers report online May 5 in Science.

The findings are the first to tie together the roles of genes and beneficial microbes in the inflammatory bowel disease, says biologist Brett Finlay of the University of British Columbia in Vancouver, who was not involved in the new work.

“This is a major step forward in this area,” he says. Human genes and friendly microbes work together to control inflammation, he says. “And when you muck that up, things can go awry.”

In Crohn’s disease, the immune system riles up too easily, trigging chronic inflammation. Scientists don’t know why exactly people’s immune systems go haywire. But researchers have linked the disease to glitches in nearly 200 genes, including ATG16L1 and NOD2, which typically help kill bad bacteria in the gut.

Researchers have also reported that people with Crohn’s have a different collection of gut microbes compared with that of healthy people, says study coauthor and Caltech microbiologist Sarkis Mazmanian.But though “there’s a huge body of literature on the genome and on the microbiome,” he says, “no one knew what the interplay was between the two.”

So his team explored a potential link using a friendly gut microbe called Bacteroides fragilis. The bacteria send out calming messages that tell the immune system to tone down inflammation. Like letters inside envelopes, these messages travel in protective pouches called outer membrane vesicles, or OMVs.

Feeding OMVs to mice typically protects them from developing inflamed colons, or colitis — but not mice lacking the Crohn’s-linked genes ATG16L1 and NOD2. When researchers treated those mice with a colitis-causing chemical, they succumbed to the disease, even after eating OMVs.

Mice with defective versions of ATG16L1 and NOD2 “can’t reap the benefits of the beneficial microbiota,” Mazmanian says.Immune cells from human patients with the defective genes didn’t respond to OMVs either.

The findings suggest that the genes that kill bad bacteria also work with good bacteria to keep people’s immune systems from going out of control, says gastroenterologist Balfour Sartor of the University of North Carolina School of Medicine in Chapel Hill. The work “opens up a new mechanism for protection,” he says.

Mazmanian says B. fragilis’ messages could potentially serve as a new treatment option for patients. That’s because patients’ cells dosed with just the contents of the OMVs (and not the protective pouch itself) actually got the message, his team found. The treatment could have fewer side effects than other therapies, because it doesn’t hamper the immune system, he says. 

Finlay cautions that more work is needed. “It’s early days,” he says. But, thenew work “gives us a whole different way of thinking about inflammatory bowel disease.”