Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Haeryfar, Mansour

Abstract

Fecal microbiota transplantation (FMT) has emerged as the most effective therapy for recurrent Clostridioides difficile infections (rCDI); yet the role of immune cells in the response to FMT remains poorly understood. Mucosa-associated invariant T (MAIT) cells are bacterial metabolite-reactive T cells found in the peripheral blood and mucosal tissues. We posited that MAIT cells are in the perfect position to respond to the influx of microbial metabolites associated with FMT. We collected peripheral blood from rCDI patients prior to FMT, 1-week post-FMT, and 1-month post-FMT, to explore if MAIT cell phenotypic characteristics or functions change following treatment. Following FMT, MAIT cells moved away from a state of exhaustion and displayed increased cytokine production. While pre-FMT MAIT cells were predominantly MAIT-17, post-FMT MAIT cells in some patients shifted to become neither MAIT-17, MAIT-1, nor MAIT-2. The data indicates that FMT may reverse MAIT cell exhaustion after a long battle with rCDI.

Summary for Lay Audience

Clostridioides difficile is a bacterium that can cause infection resulting in diarrhea, fluid loss, or even death, when it gets into the intestinal tract. Since C. difficile has multiple ways to avoid destruction by antibiotics, a new effective treatment called fecal microbiota transplantation (FMT) is being widely adopted for those with the chronic form of the disease. FMT involves taking healthy gut bacteria from one person and transferring them into the intestinal tract of a person with C. difficile infection. It is thought that the healthy bacteria take up space and nutrients, eventually forcing C. difficile out. While FMT is successful in getting rid of C. difficile in most cases, the way the immune system responds to FMT is still not well understood. One immune cell type, mucosa-associated invariant T (MAIT) cells, is found in mucosal tissues and the blood. MAIT cells also respond specifically to bacterial by-products, such as those from the FMT bacteria. We therefore theorized that MAIT cells are in the perfect position to interact with FMT. With this in mind, we drew blood from people with C. difficile infections prior to FMT, then again one week and one month post-FMT. The activation level of blood MAIT cells, as well as what types of anti-bacterial molecules they produced, were then examined. We found MAIT cells to express high levels of markers associated with exhaustion — a state where MAIT cells do not function properly— prior to FMT. Following FMT, however, MAIT cells moved away from a state of exhaustion and were able to produce higher levels of anti-bacterial molecules. My findings suggest that FMT may help to restore MAIT cells’ antibacterial functions following their battle with C. difficile. FMT can be costly and is not widely accessible at present. With improvements in our understanding of the immune response to FMT, new treatment strategies and tools to optimize or even replace FMT may emerge.

Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

Available for download on Wednesday, August 23, 2023

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