Talk abstracts
Talk on Tuesday 04:45-05:00pm submitted by Yonaida Valentine
Chemotherapy-induced changes to the gut microbiota mediate fatigue and depressive-like behavior and induces neuroinflammation.
Yonaida Valentine (The Ohio State University), Lindsay Strehle, M.S. (The Ohio State University), Audrey Duff, Ph.D. (Nationwide Childrens Hospital), Lauren Otto, Melina Seng (The Ohio State University), Michael Bailey, Ph.D. (Nationwide Childrens Hospital), Leah Pyter Ph.D. (The Ohio State University)
Abstract:
Every year, nearly 500,000 cancer patients in the U.S. receive chemotherapy as part of their treatment. However, chemotherapy induces behavioral side effects that can reduce treatment compliance and thereby increase mortality. Finding the mechanisms underlying these behavioral changes is essential to identify new treatment strategies. Previously, we have shown that chemotherapy-induced changes to the gut microbiota are sufficient to induce anxiety-like behavior and neuroinflammation in germ-free mice. Here, in a more neurodevelopmentally and immunologically healthy mouse model, we hypothesize that the chemotherapy-transformed gut microbiota induces fatigue, anxiety-like, cognitive dysfunction, and depressive-like behavior; and induces neuroinflammation. In the present study, conventional, female, C57/Bl6J mice received an antibiotic knockdown of commensal gut bacteria (2 daily intra-gastric gavages of 1.25g/kg streptomycin) and were then randomized to receive 3 intra-gastric vehicle (Veh-) or chemotherapy (Chemo-) gut-microbial transplants (GMT; i.e., transplant of gut contents from mice that were directly injected with paclitaxel chemotherapy or vehicle treatment) over 7 days. Mice were then assessed for fatigue, cognitive, anxiety-like, and depressive-like behaviors. Brain tissue was collected to assess neuroimmune morphological and gene expression changes. Fecal samples were collected for genomic sequencing and 16S rRNA fecal microbial profiles. Preliminary data showed antibiotics significantly reduced gut bacterial load, whereas GMTs significantly increased gut bacterial load. Chemo-GMT induced fatigue and depressive-like behaviors in mice. This was accompanied by increased neuroinflammation in the hippocampus (Tnfa, Tlr2, Nlrp3) and a reduction in a neuronal plasticity marker (Psd95) in the hypothalamus as measured by RT-qPCR. These results suggest that the gut microbiota mediates behavioral side effects of chemotherapy through neuroinflammatory mechanisms.
Keywords: Chemotherapy, Gut Microbiota, Neuroinflammation