An NIAID study in mice shows how the immune system prevents commensals—the microbes that naturally colonize the lining of the digestive tract—from contributing to inflammation during gut infection. The findings suggest that defects in this protective mechanism may contribute to chronic disorders such as inflammatory bowel disease (IBD). The study appears in the September 2013 issue of Cell Host & Microbe.
The human intestine is home to approximately 100 trillion commensals, which aid digestion and help protect the gut from disease-causing microbes. However, among these beneficial inhabitants are some potentially harmful species that can contribute to inflammation and cause infections. Increased levels of some of these species have been linked to IBD.
Under normal circumstances, the immune system keeps commensals in check and minimizes their contact with the moist tissue lining the gut, called the epithelium. Gastrointestinal infections can disrupt this balance and promote the outgrowth of commensal species, which can worsen gut inflammation and cause tissue damage.
To study how the immune system regulates commensals during infection, scientists led by Yasmine Belkaid, Ph.D., of the NIAID Laboratory of Parasitic Diseases, in collaboration with Philip Murphy, M.D., of the NIAID Laboratory of Molecular Immunology, infected mice with Toxoplasma gondii, a parasite that causes severe gut inflammation. Within a few days of infection, immune cells migrated to the lumen—the inner space of the intestine—and formed structures surrounding commensal bacteria. These containment structures, called casts, held high concentrations of commensals with pathogenic potential, such as E. coli. The casts prevented these inflammatory bacteria from contacting the epithelium, entering the body, and causing widespread infection.
Further studies revealed that cast formation is driven by infection-fighting immune cells called neutrophils. When the scientists treated parasite-infected mice with a neutrophil-depleting antibody, casts did not form, and the mice were more likely to die. Giving the mice antibiotics—drugs that kill bacteria but not parasites—dramatically improved their survival.
The investigators also found that commensals trigger neutrophil migration and cast formation by producing a chemical signal that interacts with a receptor on the neutrophil surface. When mice lacking this receptor were infected with T. gondii, casts did not form, and the mice died more quickly.
The researchers describe how the immune system mounts a rapid, efficient response to control commensals during gut infection. Their findings suggest that failure to develop or control this response can promote tissue injury and inflammation, which could lead to chronic disorders such as IBD.
The findings also highlight the lumen’s role in immunity. While the epithelium typically is thought of as the gut’s first line of defense, the NIAID team’s findings reveal that the lumen can actively participate in immune responses.
Additional studies are needed to assess whether these findings in mice also apply to humans. Future studies may focus on understanding how casts form in response to infection with different pathogens. The researchers also may investigate links between this immune response and IBD.
Molloy MJ, Grainger JR, Bouladoux N, Hand TW, Naik S, Quinones M, Dzutsev AK, Gao JL, Trinchieri G, Murphy PM, Belkaid Y. Intra-luminal containment of commensal outgrowth in the gut during infection-induced dysbiosis. Cell Host & Microbe DOI: 10.1016/j.chom.2013.08.003 (2013)
Dr. Belkaid’s Lab
Dr. Murphy’s Lab
Last Updated September 09, 2013
Last Reviewed September 09, 2013