A systematic assessment of the short- and long-term effects of commonly used breast cancer chemotherapeutics on the gut microbiome‒blood‒brain axis of female mice

Chemotherapy affects over 300,000 U.S. breast cancer patients, which disrupts the gut microbiome and induces gut inflammation-an effect hypothesized to drive gastrointestinal side effects (e.g., diarrhea, vomiting) experienced by 50%-80% of patients. Preclinical studies have found causal links amongst chemotherapy-induced gut microbiome disruption, systemic inflammation, and brain-mediated side effects. Therefore, the gut microbiome represents a therapeutic target to attenuate chemotherapy side effects. Because clinical populations are administered multiple chemotherapeutics in combination, a comprehensive understanding of which treatments disrupt the gut microbiome‒blood‒brain axis is lacking. Here, translationally-relevant regimens of four commonly used breast cancer chemotherapies (paclitaxel, cyclophosphamide, cisplatin, and doxorubicin) were given to adult female C57BL/6 mice, and inflammatory, metabolomics and/or bacteriome outcomes were measured in the gut, gut contents, blood, and brain tissues, along with a fatigue and anxiety-like behavioral assessment. Many inter-chemotherapy differences were observed but notable findings include prolonged circulation and central proinflammatory signals by paclitaxel and sustained disruption of the gut microbiome by cisplatin. In contrast, cyclophosphamide and doxorubicin modestly disrupted the gut microbiome‒blood‒brain axis. Taken together, this study systematically identified that paclitaxel and cisplatin most robustly disrupted the gut microbiome‒blood‒brain axis, suggesting that those treated with these drugs may benefit the most from gut-targeted interventions for associated side effects.