Mutational signatures shift induced by chemotherapeutic agents, 5-Fluorouracil and Oxaliplatin, in the gut microbiome

Abstract We developed a powerful framework for taxonomy composition and genomic variation analysis to investigate the mutagenesis effect and proliferation influence of chemotherapeutic agents, such as 5-Fluorouracil (5-FU) and Oxaliplatin (Oxi) on gut microbiota. Using the gut microbiome data of 68 time serial stool samples, we detected 1.45 million variations among the chemotherapy groups and found the drugs significantly affected mutation signatures of gut microbiota. About 786 faecal metagenomes of 755 individuals from 5 different cohorts were analyzed to build the mutation pattern of gut microbiota from health samples. Oxi notably increase transversion rate, while 5-FU reduced the rate. We also performed in vitro experiments to confirm that chemotherapeutic agents could disrupt the pattern of genetic variant in the intestinal microorganisms. Post-chemotherapy samples had specific gut microbiome signatures with higher abundance of Bacilli and a lack of anaerobic bacteria. In addition, drug-associated functional alterations were also found: metabolism changes in the 5-FU group implied that gut microbiota could provide additional NAD + to inhibit cancer cell autophagy; in the Oxi group, the ribosome and lysine biosynthesis genes were obviously enriched. According to molecular evolution analysis, traits related to protein secretion system showed evidence of strong selection pressure from the drugs, which could be a novel potential treatment strategy for chemotherapy-induced diarrhea. Our study provides a blueprint for characterizing the role of microbes and drug-microbe interaction in the gut microbiota response to chemotherapy.