Identification of Beneficial Bacteria May Lead to New Treatment for Common Infection

Pictured: Joao Xavier & Eric Pamer

Computational biologist Joao Xavier (left) and infectious diseases specialist Eric Pamer

Infection with the bacterial pathogen Clostridium difficile is a growing problem. C. diff, as it is commonly known, releases toxins that damage the lining of the large intestine, leading to abdominal pain, diarrhea, and sometimes more serious conditions that can take weeks or months to resolve and can — in rare circumstances — be fatal.

Now research from Memorial Sloan Kettering is providing support for a novel preventive strategy: using a bacterial species that is naturally found in healthy gastrointestinal tracts to prevent C. diff infections.

Now that we know which bacterial species has a protective effect, we can begin to look for ways to develop a clinical treatment.
Physician-scientist Eric Pamer

“It’s been well appreciated that the loss of normal bacteria in the intestines can lead to infection with C. diff,” says Eric Pamer, Head of the Division of General Medicine, Chief of MSK’s Infectious Diseases Service, and the senior author of a study published recently in Nature. “Now that we know which bacterial species has a protective effect, we can begin to look for ways to develop a clinical treatment.”

Restoring the Balance

Experts have known for several decades that treatment with antibiotics can destroy beneficial bacterial strains in the intestines and allow C. diff to flourish. Some antibiotics are highly associated with the development of C. diff, particularly those that kill broad swaths of commensal bacteria (the type that naturally live on or in the human body without causing harm). However, until recently it was unclear which bacterial species provide protection against C. diff infection.

Patients with C. diff infections are usually treated with more antibiotics, but this solution is associated with high rates of recurrence, occasionally leading to chronic colitis (inflammation of the colon) and the need for very prolonged additional antibiotic treatment.

Recent clinical studies have shown that fecal transplants — in which feces from a healthy donor is introduced into the colon of someone with chronic C. diff  — can lead to the eradication of C. diff infections.

But doctors have been reluctant to offer this treatment to patients who are immunocompromised, especially those undergoing bone marrow transplants (BMTs) or receiving extensive chemotherapy for leukemia or lymphoma, because it’s impossible to determine all the parts — and potentially infectious agents — in a fecal sample.

“There has been much motivation to find the components of the fecal transplant that confer resistance to C. diff,” Dr. Pamer says. “The goal of our study was to identify specific bacterial species present in the normal intestinal tract that can be used to prevent or treat C. diff infections.”

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Decreasing Susceptibility to Infection

Charlie Buffie, a graduate student in Dr. Pamer’s laboratory, worked with MSK computational biologists Joao Xavier, Vanni Bucci, and Richard Stein to analyze the DNA sequences of intestinal bacteria that were obtained from antibiotic-treated laboratory mice. By doing this, they were able to identify bacterial species that inhibit C. diff infection.

These computational tools were also used to establish, in samples from patients undergoing BMTs, correlations between specific microbes found in the intestines and how susceptible those patients were to C. diff infection.

Using these tools, the research team identified a strain found in both mice and humans called Clostridium scindens that confers resistance to C. diff. When the research team gave C. scindens to susceptible mice prior to infection with C. diff, they found that it led to lower levels of the harmful bacterium, which in turn led to a decrease in toxin production and reduction in colitis.

Before clinical trials can begin in humans, additional research in mice is needed. “One thing we still need to work out are the optimal bacteria companions for C. scindens,” Dr. Pamer says. “Our study demonstrates that it’s more effective against C. diff if it’s accompanied by three other species. It’s not surprising, because bacteria often work together to support each other in a complex environment like the human intestine.”

He adds that because C. scindens and other bacterial species associated with resistance to C. diff infection are extremely sensitive to oxygen — killed by the smallest of concentrations — investigators will need to find novel ways to administer these protective bacteria that prevent their exposure to oxygen in the air.

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This research was funded by the National Institutes of Health under grants R01 AI42135, AI95706, and DP20D008440, and the Tow Foundation.