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Immune Response to Gut Microbiota May Contribute to Crohn’s Disease

Electron microscopic image of a single human lymphocyte.
Electron microscopic image of a single human lymphocyte.

NIAID investigators have observed in mice that during gastrointestinal (GI) tract infection, the immune system not only mounts a response to harmful microbes, it also attacks a type of “good” bacteria in the gut. Their findings suggest that immune responses to gut microbiota, or commensals, induced by infection, may contribute to the development of Crohn’s disease. The study appears online in the August 23 issue of Science.

Background

The human GI tract is home to trillions of commensal bacteria, which are not known to trigger an immune response in healthy people. Investigators have suggested that the immune system does not attack gut commensals because it does not treat them as foreign invaders, but remains tolerant to their presence. Because commensals appear to play a protective role against infection and chronic disease, immune tolerance of these good bacteria seems advantageous to the host.

Genetic studies of gut commensals have revealed that they express a multitude of molecules, including inflammatory ones also expressed by harmful microbes. During infection, the products of inflammatory genes trigger an immune attack; therefore, it seems likely that the immune system could recognize and mount a response to commensal bacteria.

Recent work on gut commensals has given investigators a greater appreciation for the role these bacteria play in the development of Crohn’s disease, a condition that causes chronic inflammation in the GI tract and can significantly increase the risk of intestinal cancer. Crohn’s symptoms include abdominal pain, fever, fatigue, bloody stools, and ulcers. Medications can treat the symptoms of Crohn’s disease, but for people with severe disease, surgery may be necessary.

Understanding how the immune system distinguishes commensals from harmful microbes could provide additional clues to how these responses might contribute to the development of Crohn’s disease. 

Results of Study

To examine how the immune system responds to commensal bacteria before, during, and after infection, a study team led by Timothy Hand, Ph.D., and Yasmine Belkaid, Ph.D., in the Mucosal Immunology Section of the NIAID Laboratory of Parasitic Diseases, worked with mouse models of GI tract infection.

The team infected mice with the parasite Toxoplasma gondii, the cause of the disease toxoplasmosis. Specialized T cells in the mouse immune system cleared the parasite from the GI tract after nine days of infection. The team observed that nearly 10 percent of the T cells in the GI tract specifically attacked the parasite, but they also found that approximately 45 percent of the T cells responded to other gut microbes. This suggested that the specialized T cells may target commensal bacteria.

To focus their efforts, the team transferred immune cells from a mouse engineered to only make T cells that recognize Clostridium bacteria, a commensal that is associated with Crohn’s disease, into parasite-infected mice. The commensal-specific T cells rapidly divided in the infected mice and released a cell-signaling molecule that could target commensal bacteria. Additionally, these T cells remained in circulation after gut infection had been cleared, suggesting that they could mount a response to the commensal bacteria at a later time.

When the team transferred the commensal-specific T cells into uninfected mice, cell division and production of the cell-signaling molecule did not occur, suggesting that the immune response to commensals occurs only during infection.

Significance

The team’s findings are among the first to demonstrate that T cells in the gut mount an immune response to commensal bacteria during an infection. They also are the first to show that commensal-specific T cells remain in circulation after the infection is cleared. Based on their observations, the investigators speculate that, when uncontrolled, commensal-specific T cells may contribute to development of Crohn’s disease, but more research is needed.

Next Steps

The NIAID team continues to determine the impact that commensal-specific T cells have on health. Because the commensal-specific T cells appear to develop only after infection, the researchers also will explore whether or not infections in the gut contribute to the development of Crohn’s disease and other chronic diseases of the GI tract.

References

Hand TW, Dos Santos LM, Bouladoux N, Molloy MJ, Pagán AJ, Pepper M, Maynard CL, Elson III CO, Belkaid Y. Acute gastrointestinal infection induces long-lived microbiota-specific T cell responses. Science. Aug. 23, 2012 (online ahead of print).

Dr. Belkaid’s lab page

Crohn’s disease (from the National Library of Medicine)

Last Updated August 27, 2012

Last Reviewed August 27, 2012