Purpose: The gut microbiome is involved in antitumor immunotherapy and chemotherapy responses; however, evidence-based research on the role of gut microbiome in predicting response to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) remains scarce. This prospective, longitudinal study aimed to evaluate the feasibility of the gut microbiome in predicting nCRT responses. Experimental Design: We collected 167 fecal samples from 84 patients with LARC before and after nCRT and 31 specimens from healthy individuals for 16S rRNA sequencing. Patients were divided into responders and nonresponders according to pathologic response to nCRT. After identifying microbial biomarkers related to nCRT responses, we constructed a random forest classifier for nCRT response prediction of a training cohort of baseline samples from 37 patients and validated the classifier in another cohort of 47 patients. Results: We observed significant microbiome alterations represented by a decrease in LARC-related pathogens and an increase in Lactobacillus and Streptococcus during nCRT. Furthermore, a prominent microbiota difference between responders and nonresponders was noticed in the baseline samples. Microbes related with butyrate production, including Roseburia, Dorea, and Anaerostipes, were overrepresented in responders, whereas Coriobacteriaceae and Fusobacterium were overrepresented in nonresponders. Ten biomarkers were selected for the response-prediction classifier, including Dorea, Anaerostipes, and Streptococcus, which yielded an area under the curve value of 93.57% [95% confidence interval (CI), 85.76%–100%] in the training cohort and 73.53% (95% CI, 58.96%–88.11%) in the validation cohort. Conclusions: The gut microbiome offers novel potential biomarkers for predicting nCRT responses, which has important manifestations in the clinical management of these patients.

Approximately 60–80% of cancer patients treated with abdominopelvic radiotherapy suffer post-radiotherapy toxicities including radiation enteropathy and myelosuppression. Effective preventive and therapeutic strategies are lacking for such radiation injury. The gut microbiota holds high investigational value for deepening our understanding of the pathogenesis of radiation injury, especially radiation enteropathy which resembles inflammatory bowel disease pathophysiology and for facilitating personalized medicine by providing safer therapies tailored for cancer patients. Preclinical and clinical data consistently support that gut microbiota components including lactate-producers, SCFA-producers, indole compound-producers and Akkermansia impose intestinal and hematopoietic radio-protection. These features serve as potential predictive biomarkers for radiation injury, together with the microbial diversity which robustly predicts milder post-radiotherapy toxicities in multiple types of cancer. The accordingly developed manipulation strategies including selective microbiota transplantation, probiotics, purified functional metabolites and ligands to microbe-host interactive pathways are promising radio-protectors and radio-mitigators that merit extensive validation in clinical trials. With massive mechanistic investigations and pilot clinical trials reinforcing its translational value the gut microbiota may boost the prediction, prevention and mitigation of radiation injury. In this review, we summarize the state-of-the-art landmark researches related with radio-protection to provide illuminating insights for oncologists, gastroenterologists and laboratory scientists interested in this overlooked complexed disorder.