Hospitalized patients receiving antibiotic treatment experience a disruption in the intestinal microbiome enabling opportunistic pathogens, such as Clostridioides difficile to colonize the intestinal tract. Complications resulting from C. difficile associated disease are a major burden on the health care system costing an estimated one billion dollars and resulting in 12,000-20,000 deaths per year (11, 13). Current antibiotic treatment options have a high recurrence rate highlighting the need to develop alternative treatment strategies. Fecal microbiome transplantation (FMT) has proven to be a remarkable effective strategy for treatment of recurrent C. difficile infection (21). However, the host and microbial factors that contribute to FMT success remain poorly defined. The murine model of C. difficile infection offers insights into the mechanism of action of FMT. Data presented in this proposal demonstrates an important role for the host?s immune system, specifically CD4+ T-regulatory (TReg) cells, in supporting FMT efficacy.
In aim 1 of this proposal we will investigate the immunoregulatory mechanisms through which TReg cells shape the intestinal environment to promote FMT engraftment and C. difficile resolution. Conversely, aim 2, will assess the innate immune inflammatory mediators that shape the intestinal environment to inhibit FMT engraftment and C. difficile resolution. In parallel to murine studies, we will conduct longitudinal profiling of human immune cell populations in severe C. difficile infected patients before and after FMT.
These aims will identify immune mechanisms that support successful FMT therapy in C. difficile infection and potentially identify novel therapeutic targets in treating C. difficile associated disease. 1
The intestinal pathogen Clostridiodies difficile is most common hospital-acquired infection in the United States, and the inefficacy of current antibiotic treatment regimens highlight the need to develop alternative treatment strategies. Transplantation of fecal bacteria from a healthy donor into an infected patient?s intestinal tract has emerged as a remarkably effective and promising therapy, however, the mechanism through which beneficial bacteria act to clear C. difficile is not well understood. This proposal seeks to understand how the body?s own immune system works with the fecal transplant to support resolution of C. difficile infection. 1
