Association between Gut Microbial Change and Acute Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Definitive Radiation Therapy: A Prospective Pilot Analysis.

Abstract

The gut microbiome is an emerging biomarker that is known to have a pivotal role in the development of diverse human diseases. This prospective cohort study aimed to investigate the association between gut microbial changes and acute gastrointestinal (GI) toxicities in prostate cancer patients receiving definitive radiation therapy (RT). Seventy-nine fecal samples from 16 prostate cancer patients were analyzed. Stool samples were collected at the following timepoints: pre-RT (prRT), 2 weeks after the start of RT (RT-2w), 5 weeks after the start of RT (RT-5w), 1 month after completion of RT (poRT-1m), and 3 months after completion of RT (poRT-3m). Total RT doses were 69.6‒74.4 Gy at 2.4 Gy per fraction in the high-dose area and 45‒50.4 Gy at 1.8 Gy per fraction in the low-dose area. Alpha- and beta-diversity were estimated. We computed the microbial community polarization index (MCPI) as an indicator of RT-induced dysbiosis. A linear mixed effect model was adopted to evaluate time effects after RT. Metabolic pathway abundances were inferred using bioinformatics tools. Seven patients experienced ≥ grade 1 acute GI toxicities. Patients experiencing toxicity had lower alpha diversity, especially at RT-2w (P = 0.037) and RT-5w (P = 0.003), with the microbiota enriched in Fusobacteria, Fusobacterium, and Bacteroides fragilis. Patients receiving a large RT field had a trend of lower alpha diversity, particularly at poRT-1m (P = 0.027), with the microbiota enriched in Propionibacteriaceae, Cutibacterium, and Prevotella stercorea. Compared with the MCPI at prRT, the MCPI observed at poRT-1m in patients experiencing toxicities was significantly elevated (P = 0.007). In terms of predicted metabolic pathways, we found linearly decreasing pathways, including carbon fixation pathways in prokaryotes (P = 0.035) and the bacterial secretion system (P = 0.005), in patients who experienced toxicities. Regarding the RT field, no linear trend of functional pathways was found across timepoints. We showed RT-induced dysbiosis in the gut microbiome among patients with prostate cancer who experienced toxicities or received a large RT field. Reduced diversity and elevated RT-related MCPI could be helpful for developing individualized RT approaches. Longitudinal analysis revealed dynamic changes in several microbes and metabolic pathways, which should be validated in a whole metagenome sequencing study.