Penn Scientists Discover Microbial Transplants Require Key T Cells for Success

PHILADELPHIA— Scientists have known for more than a decade that “good bacteria” from healthy intestines can treat and ward off potentially deadly intestinal infections by Clostridium difficile bacteria. Now researchers at the Perelman School of Medicine at the University of Pennsylvania have discovered that immune cells called T_reg cells are crucial for the success of these microbial transplants.

The findings, published in Nature Communications, hint that boosting the activity of T_reg cells may be a way to improve the effectiveness of microbial transplants for C. difficile infections. Modulating the activities of key immune cells may also turn out to be a good strategy in other diseases for which microbial transplants have been considered, including cancers, obesity, inflammatory bowel disease, and diabetes.

“With this discovery we may have identified a general law that the immune system needs to be in a certain state for these microbial transplants to work,” said Michael Abt, PhD, an assistant professor of Microbiology.

C. difficile infection of the large intestine is the most common hospital-acquired infection in the United States. It often afflicts elderly people following antibiotic treatment that disrupts their normal intestinal microbe population. Although there are antibiotics that can treat “C. diff,” the continued disruption of gut microbiota and the ability of C. diff to form hardy spores means that recurrence rates are high. There are an estimated half-million cases of C. diff infection per year, of which tens of thousands are fatal.

Transplanting healthy gut bacteria from volunteers, known as microbial transplantation, or fecal microbiota transplantation (FMT)—is now a proven treatment for treating C. diff, although in 10-20 percent of cases it doesn’t work, and scientists haven’t really understood these failures.

Abt and his team, wondering about the role of the immune system in FMT success, started with a simple experiment involving one of the most common strains of lab mice. The mice normally can get C. diff disease and can be cured by FMT. However, the team engineered mice from this strain so that they lacked a gene needed for the normal development of important immune cells called T cells and B cells. They found that these mice, in whom a big part of the immune system was missing, could still get very sick from C. diff infection but could no longer be cured by FMT. This implied that some missing immune cell population was needed for FMT to work.

The team ultimately identified a type of T cell called a regulatory T cell, or T_reg cell, as the missing ingredient in FMT success: The T_reg cells work to dampen the gut inflammation caused by C. diff infection, and without them the level of inflammation is too high for the beneficial, FMT-delivered microbes to survive for long.

Abt and his colleagues suggest from this that evaluating the immune state of an intestine infected with C. diff may someday help doctors predict if FMT will succeed. Moreover, improving the anti-inflammatory activity of T_reg cells—or somehow replacing their anti-inflammatory effect if they are missing or dysfunctional—may be a viable strategy for making microbial transplants work in C. diff cases where they would otherwise fail.

“There are other intestinal diseases, such as inflammatory bowel disease, in which FMT treatment makes sense in principle, but has seemed relatively ineffective in practice,” Abt said. “This finding that certain immune cells are needed for FMT success against C. diff may be a clue to making this promising treatment work more broadly.”

The paper was co-authored by Eric Littmann, Jung-Jin Lee, Joshua Denny, Zahidul Alam, Jeffrey Maslanka, Isma Zarin, Rina Matsuda, Rebecca Carter, Bože Susac, Miriam Saffern, Bryton Fett, Lisa Mattei, Kyle Bittinger, and Michael Abt.

Funding was provided by the National Institutes of Health (R00 AI125786), the McCabe Fellowship Fund, and a PennCHOP Microbiome Pilot Grant.