Harnessing intestinal microbes to combat inflammation and infections

Despite being an everyday necessity, nutrition is something of a black box. We know that many plant-based foods are good for us, but we don't always know why. Our intestinal microbiome, which helps break down these foods once we consume them, is another black box. What role do our gut bacteria play? New research published in Cell suggests that we could get more out of our diets by harnessing intestinal microbes to break down plant compounds collectively known as phenolic glycosides. These compounds pair sugar molecules with a host of small molecules beneficial to human health.

Plants make these molecules for all different reasons - to attract pollinators, to repel herbivores, to kill bacteria. If we're eating these plants, what happens to these molecules and how do they affect us?"

Seth Rakoff-Nahoum, MD, PhD, in Boston Children's Hospital's divisions of Infectious Diseases and Gastroenterology, Hepatology and Nutrition

His study details how different intestinal microbes use a variety of specialized enzymes to metabolize specific phenolic glycosides. These enzymes chop off the sugar molecules for the microbes' own benefit, while liberating the small molecules - potentially of use to us.

Notably, the team showed that some of these small molecules help regulate intestinal inflammation and promote resistance to intestinal pathogens. Rakoff-Nahoum believes the findings could spawn new approaches to inflammatory bowel disease and debilitating intestinal Clostridioides difficile infections.

Curbing inflammation and C. diff

To explore the intestinal microbiome's nutritional role, the researchers focused on Bacteroides, a major group of bacteria in the human gut microbiome. They systematically fed a panel of seven phenolic glycosides to 52 Bacteroides and Parabacteroides strains to see which strains broke down these compounds most effectively.

"We learned which microbes are good at metabolizing plant compounds and what enzymes they use," says Rakoff-Nahoum. "We then went to mouse models of inflammatory bowel disease and C. difficile infection and showed how microbes unleash immunoregulatory and anti-colitis properties."

In the mouse experiments, certain small molecules liberated by Bacteroides enzymes selectively inhibited intestinal colonization by C. difficile. One promising molecule was resveratrol. When released from its parent molecule, polydatin (abundant in grapes and red wine), it became an antibiotic and inhibited C. difficile in a mouse model.

Another compound, salicin, derived from willow bark, is best known as the active compound in aspirin when transformed to salicylic acid in the liver. But when activated by Bacteroides in the intestine, it releases saligenin, which regulates intestinal homeostasis and balances the immune response. The Bacteroides species that produced the necessary enzyme protected against colitis in mice, but species without this enzyme did not. Saligenin alone was also protective.

"We gave salicin from willow bark to mice and found it could be used to treat inflammation," says Rakoff-Nahoum. "The small molecule was kept intact and was bioactive. This is using your microbiome to get the health effects of diet."

Setting up clinical development

The researchers hope to see some of their discoveries tested in therapeutic models. Treatments could pair plant phenolic glycosides with the bacterial enzymes that metabolize them or with the bacteria directly. Rakoff-Nahoum has applied for patents for their work around IBD and C. difficile infection.

"In my mind, this paper opens up a field and has the potential to have major therapeutic ramifications," says Scott Snapper, MD, PhD, chief of the Division of Gastroenterology, Hepatology and Nutrition at Boston Children's.