Commensals Help Regulate Immune Responses During Inflammation
NIAID Scientists Describe Commensal-Host Dialogue in Mouse Model of Gut Inflammation
A neutrophil (left) and a monocyte (right). Credit: CDC
Results from an NIAID study suggest that commensals—the microbes that naturally colonize the moist linings of the digestive tract—trigger events that regulate their own disease-causing potential during inflammation. Understanding how commensals and the immune system interact when the gut is inflamed could help scientists develop new strategies to treat gastrointestinal disorders such as Crohn’s disease. The study appears in the May 26, 2013, online issue of Nature Medicine.
The human gut harbors trillions of commensal bacteria, which help protect the body by boosting its immune response to invading pathogens. In a healthy gut, a complex communications network helps ensure that the immune system does not attack these helpful microbial inhabitants. However, events that cause the immune system to mount an inflammatory response, such as infection, can disrupt this network. In some cases, commensals may trigger an immune response, which can lead to tissue damage and contribute to the development of chronic inflammatory diseases.
Results of Study
To examine the roles of commensals during inflammation, NIAID researchers John Grainger, Ph.D., and Yasmine Belkaid, Ph.D., and collaborators studied mice orally infected with the parasite Toxoplasma gondii, which causes gut inflammation. The scientists observed that monocytes—immune cells recruited to sites of inflammation—expressed genes and proteins involved in regulating the immune response. In particular, they produced large amounts of a type of molecular messenger called a prostaglandin. In addition to playing a key role in promoting inflammation, pain, and fever, prostaglandins produced at sites of tissue damage can suppress the immune system.
The researchers found that monocytes from regular mice began to produce more prostaglandin when stimulated with commensals from an inflamed mouse gut, suggesting that commensals directly influence immune regulation during inflammation. In contrast, when the investigators studied gut inflammation in germ-free mice—mice bred with no naturally occurring microbes in the gut or on the skin—they found that the monocytes generated much smaller amounts of prostaglandin.
The scientists next explored the effects of prostaglandin production and found that regulatory monocytes suppress the action of immune cells called neutrophils. Neutrophils help clear the body of infectious invaders, but they also release harmful chemicals that can cause tissue injury. Mice given non-steroidal anti-inflammatory drugs (NSAIDs), which block prostaglandin production, had more neutrophil-mediated gut damage and were more likely to die following T. gondii infection than mice that did not receive the drugs.
The NIAID team’s findings are the first to demonstrate a commensal-induced regulatory function for monocytes during an inflammatory response. They also are the first to show that monocyte-produced prostaglandin can rein in tissue damage caused by neutrophils. Understanding the regulation of the immune system during inflammation may inform the development of therapies that limit gut damage.
The results also may explain why NSAIDs such as aspirin sometimes cause gastrointestinal problems. By blocking the function of the enzymes that produce prostaglandins, NSAIDs can prevent monocytes from keeping neutrophils in check during inflammation, allowing activated neutrophils to release their chemical irritants.
The NIAID researchers plan to investigate at a molecular level how commensals influence monocytes to adopt regulatory features during gut inflammation. By unraveling the complex interactions between monocytes and commensals, they hope to identify potential drug targets for treatment of gastrointestinal disorders such as Crohn’s disease.
Grainger JR, Wohlfert EA, Fuss IJ, Bouladoux N, Askenase MH, Legrand F, Koo LY, Brenchley JM, Fraser IDC, Belkaid Y. Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nature Medicine DOI: 10.1038/nm.3189 (2013)
Dr. Belkaid’s lab page