Chemotherapy-driven dysbiosis in the intestinal microbiome.

Abstract

Chemotherapy is commonly used as myeloablative conditioning treatment to prepare patients for haematopoietic stem cell transplantation (HSCT). Chemotherapy leads to several side effects, with gastrointestinal (GI) mucositis being one of the most frequent. Current models of GI mucositis pathophysiology are generally silent on the role of the intestinal microbiome. To identify functional mechanisms by which the intestinal microbiome may play a key role in the pathophysiology of GI mucositis, we applied high-throughput DNA-sequencing analysis to identify microbes and microbial functions that are modulated following chemotherapy. We amplified and sequenced 16S rRNA genes from faecal samples before and after chemotherapy in 28 patients with non-Hodgkin's lymphoma who received the same myeloablative conditioning regimen and no other concomitant therapy such as antibiotics. We found that faecal samples collected after chemotherapy exhibited significant decreases in abundances of Firmicutes (P=0.0002) and Actinobacteria (P=0.002) and significant increases in abundances of Proteobacteria (P= 0.0002) compared to samples collected before chemotherapy. Following chemotherapy, patients had reduced capacity for nucleotide metabolism (P=0.0001), energy metabolism (P=0.001), metabolism of cofactors and vitamins (P=0.006), and increased capacity for glycan metabolism (P= 0.0002), signal transduction (P=0.0002) and xenobiotics biodegradation (P=0.002). Our study identifies a severe compositional and functional imbalance in the gut microbial community associated with chemotherapy-induced GI mucositis. The functional pathways implicated in our analysis suggest potential directions for the development of intestinal microbiome-targeted interventions in cancer patients.