The Microbiome and Radiation Induced-Bowel Injury: Evidence for Potential Mechanistic Role in Disease Pathogenesis

Abstract

Radiotherapy has played a major role in both the curative and palliative treatment of cancer patients for decades. However, its toxic effect to the surrounding normal healthy tissue remains a major drawback. In cases of intra-abdominal and/or pelvic malignancy, healthy bowel is inevitably included in the radiation field, causing undesirable consequences that subsequently manifest as radiation-induced bowel injury, which is associated with significant morbidity and mortality. The pathophysiology of radiation-induced bowel injury is poorly understood, although we now know that it derives from a complex interplay of epithelial injury and alterations in the enteric immune, nervous, and vascular systems in genetically predisposed individuals. Furthermore, evidence supporting a pivotal role for the gut microbiota in the development of radiation-induced bowel injury has been growing. In this review, we aim to appraise our current understanding of radiation-induced bowel injury and the role of the microbiome in its pathogenesis as well as prevention and treatment. Greater understanding of the relationship between the disease mechanism of radiation-induced bowel injury and gut microbiome might shed light on potential future prevention and treatment strategies through the modification of a patient's gut microbiome.

Keywords: cancer management complications; microbiota; pelvic radiation disease; probiotics; radiation enteritis; radiation enteropathy; radiation-induced bowel injury; radiotherapy.

Figure 1

Clinical course of patients undergoing radiotherapy to abdominopelvic region and consequential development of radiation-induced bowel injury over time.

Figure 2

Schematic representation of radiation-induced intestinal injury. (A): In healthy gut, crypts are sterile with intact mucosa. Lgr5⁺ stem cells proliferate and cells migrate upwards to provide differentiated epithelial cells of the villi. Bmi1⁺ stem cells located at the +4 position remain quiescent. (B): In the acute phase of radiation-induced injury, there is loss of epithelial barrier integrity, leading to an influx of antigenic material, including microorganisms into the lamina propria. This induces inflammation orchestrated by macrophages, dendritic cells, and recruited neutrophils from the circulation. Further inflammation is caused by endothelial cell damage and the release of thrombin. Mitotically active Lgr5⁺ cells undergo apoptosis where as Bmi1⁺ cells at the +4 position are resistant to radiation insult and acquire an Lgr5⁺ phenotype to act as a stem cell reservoir. (C): Despite epithelial barrier restoration, during the chronic phase of injury, there is an increase in the TGF-β that is secreted by macrophages and neutrophils, which promotes the differentiation of the fibroblast into myofibroblast, leading to collagen deposition and fibrogenesis.