Changes in gut, microbiome, and cognition after doxorubicin, cyclophosphamide, and paclitaxel chemotherapy treatment.

Abstract

Over 317,000 new cases of breast cancer will be diagnosed in 2025, making it the most diagnosed cancer among women in the United States. Advancements in treatment options such as chemotherapy and radiation have resulted in a 5-year survival rate of 91%. Upwards of 78% of the 4.1 million breast cancer survivors currently living in the United States report chemotherapy induced cognitive impairment (CICI), or "chemobrain". CICI defined as an impairment in memory, learning, executive function, and attention following chemotherapy treatment. There is a need for a better understanding of the long-term side effects of these treatments and the impact these may have on the quality of life for these survivors. In this study, we used a translational mouse model to study cognitive decline via intraperitoneal injections of the combination chemotherapy AC-T: Doxorubicin (DOX), Cyclophosphamide (CYP), and Paclitaxel (PTX). Mice underwent behavior tests to assess social memory and anxiety 30 days after the last AC-T injection. AC-T treated mice revealed behavioral deficits in social memory and an increase in anxiety-like behavior. RNA-sequencing and western blot analysis revealed negatively altered expression of transcripts associated with neurogenesis, axonal guidance, neurotransmission, and protein IEGs such as Arc, c-Fos, and Egr-1, respectively. Proteomics indicated increases in inflammatory markers in intestinal tissue, which also coincided with changes in intestinal morphology of AC-T treated mice. The gut microbiota of AC-T treated mice showed became dysbiotic. This study provides a multi-omic overview of the effects of AC-T treatment on cognition and intestinal inflammation and morphology.