U-M researchers explore prevention measures, treatments for C. difficile infection

Team to explore how C. difficile causes illness, how gut microbiota and immune response influence who is vulnerable

Clostridium difficile, a wily, familiar bacterium, causes a growing number of serious infections in U.S. hospitals and nursing homes. With a $7.5 million, five-year award from the National Institutes of Health, University of Michigan researchers plan to discover what factors in the microbe and in patients make C. difficile a formidable, costly problem. C. difficile infects nearly a half-million Americans each year. U-M scientists and clinicians from many disciplines will conduct three interrelated projects that will focus on:

1. the pathogen's genetic variations, to understand how pathogen variation leads to different disease outcomes
2. the beneficial gut microbiota that, when altered by antibiotics, leave patients vulnerable to infection
3. the human immune response to C. difficile infection.

The deeper knowledge should lead to better prevention measures, treatments and ways to keep infections from recurring, says U-M infectious disease specialist Vincent B. Young, M.D., Ph.D., who will direct the effort.

"If we can identify a deficiency in the host response, we may be able to develop a vaccine to compensate," Young says. "With increased knowledge of how a person's beneficial microbiota are altered by antibiotics, we can develop ways to give back microbiota that keep C. difficile in check." Young is associate professor in the U-M departments of internal medicine and microbiology and immunology.

C. difficile infections have doubled and grown more severe in recent years. Each year, 215,000 people in the United States are diagnosed with C. difficile infections while in hospitals or after a hospital stay. Another 263,000 develop C. difficile infections in nursing homes. The disease causes 28,500 deaths annually, according to the Centers for Disease Control and Prevention.

C. difficile infection causes mild to severe symptoms ranging from diarrhea to life-threatening colon inflammation.

Despite the availability of antibiotics to treat it, C. difficile increasingly recurs in some people. In contrast to many other hospital-acquired infections, recurrent C. difficile does not arise through antibiotic resistance, but through long-term changes in the makeup of the normal microbial inhabitants of the gut.

The multidisciplinary effort at U-M is one of four Cooperative Research Centers nationwide that will form the NIH-sponsored Enterics Research Investigational Network. The work brings together investigators with expertise in microbiology, immunology, clinical medicine, epidemiology, microbial ecology, evolutionary biology, animal modeling and bioinformatics. U-M's three interrelated projects tackle specific aspects of C. difficile pathogenesis.

Young will lead the overall consortium at U -M and will direct a project on the microbial ecology and molecular pathogenesis of C. difficile infection.

Another project, which explores the epidemiology and genomics of C. difficile infections, will involve collecting specimens from inpatients and outpatients at U-M Hospitals and Health Centers to discover the relationship between genetic factors of the pathogen and patient outcomes. David M. Aronoff, M.D., assistant professor of internal medicine in infectious diseases, will lead this effort.

Gary Huffnagle, Ph.D., U-M professor of microbiology and immunology and pulmonary and critical care, is co-principal investigator leading the final project, which will examine the interplay between host immunity and the pathogenesis of C. difficile.

Other U-M researchers involved in the research include: Jun Li, Ph.D.; Philip Hanna, Ph.D.; Brian K. Janes, Ph. D.; Patrick Schloss, Ph.D.; John Kao, M.D.; Andrzej Galecki, M.D., Ph.D.; Seth Walk, Ph.D.; Laraine L. Washer, M.D.; and Preeti N. Malani, M.D., who also is a research scientist with the Veterans Affairs Ann Arbor Healthcare System.