Fecal microbial transplantation for chemotherapy behavioral side effects

PROJECT SUMMARY/ABSTRACT Mental side effects of chemotherapy reduce quality of life and treatment dosing, thereby increasing mortality. Current supportive care treatments are ineffective, thus identifying new interventions to prevent or reduce these adverse side effects are crucial. We and others have recently hypothesized that gut dysbiosis may contribute to the behavioral side effects of chemotherapy. Our long-term goal is develop novel microbial-based treatments for the devastating side effects of the large and growing populations of chemotherapy-treated patients. The gut microbial community is dramatically altered by chemotherapy and has recently been shown to communicate with the brain to affect behavior. Indeed, we have previously published that altered composition of the gut microbiota due to chemotherapy in mice drives central and systemic inflammation resulting in selective behavioral side effects. Thus, the overall objective here is to determine the potential and feasibility of using fecal microbial trans- plant (FMT) as an intervention for chemotherapy behavioral side effects. Three specific aims are proposed to study this objective using our murine chemotherapy model (Aims 1 & 2) and a feasibility pilot clinical trial in breast cancer patients receiving chemotherapy (Aim 3). Aim 1 will quantify the efficacy of healthy FMTs in ameliorating sickness and cognitive behaviors during chemotherapy. Efficacy of autoFMT, alloFMT, or saline delivered in a preventative or therapeutic paradigm on sickness and cognitive behaviors will be assessed during chemotherapy treatment in mice after mammary tumor resection. Aim 2 will identify the systemic and neurobiological correlates of FMT interventions during chemotherapy. The efficacy of the FMT treatments on systemic and central inflam- matory signals, and the specific role of microglia, will be assessed during chemotherapy in mice after tumor resection. Aim 3 will pilot the feasibility of investigating the therapeutic potential for FMT to alleviate behavioral and gastrointestinal chemotherapy side effects in early-stage breast cancer patients. A small group of patients receiving chemotherapy will undergo an autoFMT or standard of care. Side effects will be assessed before and after FMT. The proposed research is conceptually innovative and our interdisciplinary team will be the first to use novel therapeutic FMT for chemotherapy-induced behavioral side effects in a combined basic and clinical approach. This research project will provide the necessary mechanistic and clinical foundation for future pro- posals focused on larger clinical FMT trials. This is the first step along a microbial research arc that has the potential to alter how common chemotherapy drugs are administered.