Gut microbe provokes release of inflammatory substance

Scientists may have discovered why Ruminococcus gnavus, shown here, has been linked to flare-ups of Crohn’s disease. Susanna M. Hamilton, Broad Communications; Matthew Henke

Crohn’s disease is a chronic condition that causes inflammation and ulcers in the intestine. The most common symptoms are cramping, belly pain, diarrhea, fever, and weight loss. Some people have severe flare-ups of disease with crippling pain. Treatment options include antibiotics, steroids, and other medicines. Eventually, surgery may be needed to remove diseased areas of the intestine.

Crohn’s disease is caused by something unknown that triggers the immune system to mistakenly attack the intestine. The immune system’s response causes inflammation, leading to symptoms of Crohn’s disease. Previous studies suggest that certain gut microbes may play a role in the disease. Other potential factors include a family history of Crohn’s disease and a diet high in fat.

Experts think microbes may be important in the immune response because certain bacteria, such as Ruminococcus gnavus, are found in higher proportions in people with the disease than without. R. gnavus can become the most common species of bacteria in the gut when the disease flares up. Plus, R. gnavus lives in the mucus layer of the intestine, where the immune system may be more likely to react to it.

To investigate the role of R. gnavus in Crohn’s disease, a team of scientists led by Drs. Jon Clardy and Matthew Henke of Harvard Medical School tested whether the microbe could trigger an immune reaction. The work was funded in part by NIH’s National Center for Complementary and Integrative Health (NCCIH) and National Institute of General Medical Sciences (NIGMS). Results were published on June 10, 2019, in the Proceedings of the National Academy of Sciences.

The researchers grew R. gnavus in a special broth and tested the mixture of molecules that the bacteria made for activity. To do this, they used mouse immune cells known as dendritic cells. The team found that the mixture could stimulate dendritic cells to produce an inflammatory molecule called TNF-alpha.

The team then isolated and purified the molecule responsible for this immune cell activation. The molecule is a type of glucorhamnan, a polysaccharide (large sugar molecule) made up of the sugars glucose and rhamnose. The more glucorhamnan that mouse dendritic cells were given, the more TNF-alpha the cells made.

Experiments using dendritic cells from genetically modified mice showed that the glucorhamnan worked via a protein called toll-like receptor 4, or TLR4. The team was also able to pinpoint the gene cluster most likely responsible for making the glucorhamnan.

Together, these findings suggest that Crohn’s disease may be triggered by a glucorhamnan made by the gut microbe R. gnavus, which then stimulates dendritic cells to make TNF-alpha. More research is needed to confirm that this glucorhamnan is found in bacteria from people with Crohn’s disease.

“This is a distinct molecule that represents the potential link between gut microbes and an inflammatory disease,” Henke says. “If we can track a single patient and see that the genes for this polysaccharide become expressed before disease symptoms get worse, that’s really powerful.”

—by Geri Piazza