The Interplay among Radiation Therapy, Antibiotics and the Microbiota: Impact on Cancer Treatment Outcomes

Abstract

Radiation therapy has been used for more than a century, either alone or in combination with other therapeutic modalities, to treat most types of cancer. On average, radiation therapy is included in the treatment plans for over 50% of all cancer patients, and it is estimated to contribute to about 40% of curative protocols, a success rate that may reach 90%, or higher, for certain tumor types, particularly on patients diagnosed at early disease stages. A growing body of research provides solid support for the existence of bidirectional interaction between radiation exposure and the human microbiota. Radiation treatment causes quantitative and qualitative changes in the gut microbiota composition, often leading to an increased abundance of potentially hazardous or pathogenic microbes and a concomitant decrease in commensal bacteria. In turn, the resulting dysbiotic microbiota becomes an important contributor to worsen the adverse events caused in patients by the inflammatory process triggered by the radiation treatment and a significant determinant of the radiation therapy anti-tumor effectiveness. Antibiotics, which are frequently included as prophylactic agents in cancer treatment protocols to prevent patient infections, may affect the radiation/microbiota interaction through mechanisms involving both their antimicrobial activity, as a mediator of microbiota imbalances, and their dual capacity to act as pro- or anti-tumorigenic effectors and, consequently, as critical determinants of radiation therapy outcomes. In this scenario, it becomes important to introduce the use of probiotics and/or other agents that may stabilize the healthy microbiota before patients are exposed to radiation. Ultimately, newly developed methodologies may facilitate performing personalized microbiota screenings on patients before radiation therapy as an accurate way to identify which antibiotics may be used, if needed, and to inform the overall treatment planning. This review examines currently available data on these issues from the perspective of improving radiation therapy outcomes.

The influence of antibiotic administration on the outcomes of head-and-neck squamous cell carcinoma patients undergoing definitive (chemo)radiation

“…So far, some preclinical and few small clinical studies have suggested that the gut microbiome can modulate the anti-tumor and normal tissue effects of radiotherapy [ 16 , 27 – 30 ]. For instance, Crawford and Gordon could detect a radioprotective role of fasting-induced adipose factor, whose expression is suppressed by gut microbiota, on the intestinal epithelium [ 16 ].…”

“…In this context, the risk for severe infection-related complications, for which HNSCC patients often exhibit risk factors such as lymphopenia and malnutrition, must be critically weighted against the potential negative microbiome alterations caused by antibiotics [ 35 ]. In the future, (tailored) administration of probiotics or fecal microbiome transfers may be other approaches to address antibiotics-induced microbiome alterations; however, so far, these approaches are mainly examined with the aim to alleviate radiotherapy-induced normal tissue toxicities but not to increase the anti-tumor efficacy of radiotherapy (reviewed in [ 21 ] and [ 30 ]). At least for immune checkpoint inhibitor treatment, there are preclinical and early clinical studies showing the potential of those approaches to increase the anti-tumor immune response [ 13 , 36 , 37 ]…”

“…In addition to the microbiome-influencing abilities of antibiotics, their potential anti-tumor and radiosensitizing effects of antibiotics must be considered. For instance, doxycycline (which was used in only one case in our cohort) was found to radiosensitize cancer stem-like cells by a factor of 4.5 in vitro [ 22 , 30 ]. Other antibiotics that were reported to enhance the anti-tumor effects of radiotherapy are cephalosporins [ 23 ], which were the most common antibiotic type in our cohort.…”

Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications

“…A bidirectional relationship between RT and the gut microbiota exists. 341 One of the adverse events of radiotherapy is gut microbiota dysbiosis, which is typically characterized by a relative decrease in the richness of favorable microbes, e.g., Bifidobacterium , and an increase in the relative richness of harmful microorganisms such as Fusobacteria and Proteobacteria , 342 and these changes in the composition of gut microbiota in turn exacerbates radiation-related complications, such as radiation enteropathy. 343 , 344 However, the presence of some commensal microbes is critical for improving the efficacy of radiotherapy and moderating RT-related adverse events.…”

Gut microbiota: A novel and potential target for radioimmunotherapy in colorectal cancer

“…Second, radiation exposure can cause the formation of ROS, which are chemically active due to their unpaired electrons and can damage the DNA and other cellular structures of the intestinal microbiota, thereby triggering changes in the bacterial flora ( 81 ). In addition, the various microorganisms that make up the intestinal microbiota have different intrinsic radio-sensitivities ( 82 ), so radiation exposure can alter the composition and relative proportions of the microbiota.…”