Radiotherapy and the gut microbiome: facts and fiction

Abstract

An ever-growing body of evidence has linked the gut microbiome with both the effectiveness and the toxicity of cancer therapies. Radiotherapy is an effective way to treat tumors, although large variations exist among patients in tumor radio-responsiveness and in the incidence and severity of radiotherapy-induced side effects. Relatively little is known about whether and how the microbiome regulates the response to radiotherapy. Gut microbiota may be an important player in modulating "hot" versus "cold" tumor microenvironment, ultimately affecting treatment efficacy. The interaction of the gut microbiome and radiotherapy is a bidirectional function, in that radiotherapy can disrupt the microbiome and those disruptions can influence the effectiveness of the anticancer treatments. Limited data have shown that interactions between the radiation and the microbiome can have positive effects on oncotherapy. On the other hand, exposure to ionizing radiation leads to changes in the gut microbiome that contribute to radiation enteropathy. The gut microbiome can influence radiation-induced gastrointestinal mucositis through two mechanisms including translocation and dysbiosis. We propose that the gut microbiome can be modified to maximize the response to treatment and minimize adverse effects through the use of personalized probiotics, prebiotics, or fecal microbial transplantation. 16S rRNA sequencing is the most commonly used approach to investigate distribution and diversity of gut microbiome between individuals though it only identifies bacteria level other than strain level. The functional gut microbiome can be studied using methods involving metagenomics, metatranscriptomics, metaproteomics, as well as metabolomics. Multiple '-omic' approaches can be applied simultaneously to the same sample to obtain integrated results. That said, challenges and remaining unknowns in the future that persist at this time include the mechanisms by which the gut microbiome affects radiosensitivity, interactions between the gut microbiome and combination treatments, the role of the gut microbiome with regard to predictive and prognostic biomarkers, the need for multi "-omic" approach for in-depth exploration of functional changes and their effects on host-microbiome interactions, and interactions between gut microbiome, microbial metabolites and immune microenvironment.

Fig. 1

The potential mechanisms of the gut microbiome regulating the response to radiotherapy. Notes: Radiotherapy may reshape tumor microenvironment by microbiome, which involve the unbalance of anti-inflammatory and pro-inflammatory cell and their corresponding cytokines. Oral probiotics, prebiotics, drug interventions and FMT may maintain balance in the gut microbiome and then reshape the tumor microenvironment. Other gut microbiome related mechanisms on regulating the response to radiotherapy include circadian rhythms, FIAF production, autophagy regulation, inflammation, production of SCFAs and butyrate and cancer-associated fibroblasts etc. RT radiotherapy, DC dendritic cells, IL interleukin, NK natural killer cells, TGF tumor growth factor, MDSC myeloid-derived suppressor cells, TNF tumor necrosis factor, IFN interferon, FMT fecal microbial transplant, FIAF fasting-induced adipose factor, SCFA short-chain fatty acids

Fig. 2

The potential mechanisms of the gut microbiome in radiation-induced intestinal mucositis. Notes: The gut microbiome can influence radiation-induced gastrointestinal mucositis mainly through two mechanisms: translocation and dysbiosis. Radiation disrupts the intestinal barriers and the mucus layer and causes bacterial translocation, resulting in activation of an inflammatory response. Dysbiosis, whether caused by radiation or other factors, can influence both local and systemic immune responses. Another potential mechanism by which TLR has protective effects against radiation is activation of NF-κB signaling, which is essential for the protection of the gut against radiation-induced apoptosis. RT radiotherapy, TLR toll-like receptor, NF-κB nuclear factor-kappa B, DC dendritic cells, NK natural killer cells

Fig. 3

Crosstalks between gut microbiome, microbial metabolites and immune microenvironment may explain the underlying mechanism of gut immune alliance. Notes: Microbial metabolites induced by radiotherapy could enter the bloodstream transported to the liver, brain and other organs of the body. Immune microenvironment is thus changed and may modulate radio-sensitivity and radiation injury. GLP-1 glucagon-like peptide-1, PYY peptide tyrosine tyrosine, LPS lipopolysaccharide, IPA indolepropionic acid, APC antigen-presenting cell, TLR toll-like receptor