Diet Affects Autoinflammatory Disease Via Gut Microbes

At a Glance

• A study in mice revealed how diet-induced changes to intestinal bacteria can influence susceptibility to autoinflammatory disease.
• The results could help guide new approaches to treat autoinflammatory diseases in susceptible people.

In autoinflammatory diseases, the innate immune system, for unknown reasons, becomes activated and triggers inflammation. This part of the immune system is the body’s rapid first line of defense against infection. The short-term heat, swelling, and redness of inflammation are a normal part of the body’s protective response to injury or infection. But prolonged inflammation can seriously damage the body.

Prevotella in the gut has been linked to inflammation. Image by Yamanaka et al., courtesy of BMC Microbiol., 2009, 9:11.

Recent research suggests that diet can affect certain autoimmune diseases. A team led by Dr. Thirumala-Devi Kanneganti of St. Jude Children’s Research Hospital studied mutant mice that develop a condition resembling chronic recurrent multifocal osteomyelitis in humans. This rare inflammatory bone condition is marked by pain and joint swelling, and can cause slow growth and permanent bone deformity. Their study was funded in part by NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Cancer Institute (NCI), and National Institute of Allergy and Infectious Diseases (NIAID). It appeared online on September 28, 2014, in Nature.

As expected, mutant mice fed a regular diet developed hind paw inflammation, bone erosion, and enlarged lymph nodes by day 100. Tissue analysis showed infiltrating immune cells, such as neutrophils, and significant bone destruction. However, mutant mice fed a diet rich in saturated fats and cholesterol were largely protected.

Diets high in fat and cholesterol are known to cause changes in gut microbe communities. The team’s analysis showed that the intestinal microbiota in regular-fed mutant mice was markedly different from that of healthy wild-type mice. Some of the differences, such as increased Prevotella bacteria in the mutant animals, have been linked to inflammation. These changes were significantly reduced in mutant mice fed a high-fat diet.

Antibiotics protected the regular-diet mutant mice from osteomyelitis. To further explore the role of the intestinal microbiota in autoinflammatory disease, the team performed fecal transplantation studies. Transplanting the microbiota of regular-fed mutant mice to young mice boostedPrevotella levels and sped osteomyelitis. Conversely, transplanting the microbiota of high-fat-fed mice into young mice limited Prevotella and protected mice from osteomyelitis.

To better understand the mechanisms involved, the researchers analyzed levels of interleukin-1β (IL-1β), which has previously been linked to inflammatory bone disease, in the animals’ footpads. IL-1β protein concentrations were significantly increased in the footpads of regular-fed mutant mice, whereas levels in those fed a high-fat diet were comparable to healthy controls. This suggests that the high-fat diet suppressed osteomyelitis in the susceptible mice by affecting levels of IL-1β.

Together, these findings show that diet affects osteomyelitis in susceptible mice by altering the intestinal microbiota, which in turn influence IL-1β levels in distant neutrophils. Exactly how the microbiota affect IL-1β levels remains to be determined.

“Multiple lines of evidence suggest that dietary consumption can impact human disease; however, the scientific mechanisms involved have been lacking,” Kanneganti says. “Our results demonstrate that diet can influence immune-mediated disorders by shaping the composition of commensal bacteria.”

—by Harrison Wein, Ph.D.