Ángela Del Águila, Jeremy T Beales, Jana L Fisher, Nicholas R Lozier, Krithika Dama, Yonaida A Valentine, Zoe M Tapp, Sagar D Sardesai, Nicole O Williams, Margaret E Gatti-Mays, Daniel G Stover, Preeti K Sudheendra, Robert Wesolowski, Audrey F Duff, Ai Ni, Michael T Bailey, Leah M Pyter
These findings are consistent with a role for gut microbes in chemotherapy-induced fatigue and suggest that FMT is not universally beneficial, with effects varying by chemotherapy drug.
BACKGROUND: Fatigue is a common and debilitating side effect of chemotherapy, negatively affecting treatment adherence and survival. Chemotherapy alters gut microbiome composition, and accumulating evidence suggests that gut microbes contribute to chemotherapy-induced fatigue. Because the gut microbiome is modifiable through targeted interventions, such as fecal microbiota transplantation (FMT), microbiome modulation has emerged as a potential strategy to mitigate treatment-related toxicities. To understand the impact of FMT interventions across the gut-brain axis, studying rodent chemotherapy models that simultaneously capture behavioral side effects and gastrointestinal pathology is warranted.
METHODS: Patient-reported fatigue and diarrhea were assessed in breast cancer patients before and during chemotherapy (n = 67). In parallel, mice were treated with chemotherapy (5-fluorouracil [5-FU] or paclitaxel) with or without FMT derived from pre-chemotherapy fecal material. Outcomes included fatigue (in-cage locomotion and voluntary wheel running), gut microbiome composition (16S rRNA sequencing), intestinal and brain gene/protein expression (RT-qPCR, single-cell RNA sequencing, and/or multiplex electrochemiluminescence assay), and circulating inflammatory markers.
RESULTS: In patients, increased fatigue during chemotherapy was associated with worse diarrhea and shifts in gut microbiome composition. In mice receiving 5-FU, FMT produced mild-to-moderate benefits, most notably preserving body mass, with milder and transient benefits for fatigue. FMT partially normalized gut bacterial taxa, reduced 5-FU-induced colonic Il1b expression, and prevented chemotherapy-related increases in brain Aqp4. FMT did not attenuate other inflammatory effects induced by 5-FU or paclitaxel.
CONCLUSION: These findings are consistent with a role for gut microbes in chemotherapy-induced fatigue and suggest that FMT is not universally beneficial, with effects varying by chemotherapy drug.