Increased Diversity of the Intestinal Microbiome Predicts for Lower Rates of Patient Reported Acute Gastrointestinal Toxicity in Women Receiving Radiation Therapy for Cervical Cancer

Abstract

Patients receiving pelvic radiation for cervical cancer experience high rates of acute gastrointestinal toxicity. The microbial flora has been shown to impact toxicity from cancer treatment but has not been evaluated serially during the course of radiation therapy. We aim to investigate whether or not intestinal microbiome diversity predicts for patient reported GI toxicity. We designed a prospective study to characterize changes in the intestinal microbiome and their correlation to patient-reported gastrointestinal (GI) toxicity during the course of radiation therapy (RT). Rectal and cervical samples were obtained from 20 patients before and during RT (week 1, 3 and 5). DNA was isolated from patient swabs and analyzed with 16S r RNA sequencing performed in collaboration with the Alkek Center for Metagenomics and Microbiome Research (CMMR) at Baylor College of Medicine. GI toxicity was assessed with the EPIC instrument to evaluate frequency, urgency, and discomfort associated with bowel function with higher scores representing better GI function. Shannon diversity index was used to characterize alpha (within sample) diversity with comparison of changes over time and toxicity scores performed using linear regression. Weighted UniFrac principle coordinates analysis (PCOa) was used to compare beta (between sample) diversity between samples using the PERMANOVA test. On univariate linear regression for rectal samples, increased EPIC toxicity score was inversely associated with time (B = -4.95; P<.0001) and directly associated with increased Shannon diversity index (B = 11.46; P = .006). On multivariate linear regression, increased Shannon diversity index was independently associated with increased EPIC toxicity score (B = 8.46; P = 0.0001) as was time (B = -4.41; P<.0001) and sample type (Cervix: Rectum B = 4.84; P = 0.01). No individual OTU’s were significantly associated with increased toxicity. On PCOa analysis, rectal OTU composition and structure was significantly different for patients with EPIC scores greater than and less than the median (R2 = 0.045; P = 0.006). Fractionated radiation treatment decreases the diversity of intestinal microbial flora over time. Decreased diversity was independently associated with higher toxicity, even when adjusted for time. Interventions to increase flora diversity may reduce acute GI toxicity from radiation.