Dissecting the role of the gut microbiome and fecal microbiota transplantation in radio- and immunotherapy treatment of colorectal cancer.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and poses a major burden on the human health worldwide. At the moment, treatment of CRC consists of surgery in combination with (neo)adjuvant chemotherapy and/or radiotherapy. More recently, immune checkpoint blockers (ICBs) have also been approved for CRC treatment. In addition, recent studies have shown that radiotherapy and ICBs act synergistically, with radiotherapy stimulating the immune system that is activated by ICBs. However, both treatments are also associated with severe toxicity and efficacy issues, which can lead to temporary or permanent discontinuation of these treatment programs. There's growing evidence pointing to the gut microbiome playing a role in these issues. Some microorganisms seem to contribute to radiotherapy-associated toxicity and hinder ICB efficacy, while others seem to reduce radiotherapy-associated toxicity or enhance ICB efficacy. Consequently, fecal microbiota transplantation (FMT) has been applied to reduce radio- and immunotherapy-related toxicity and enhance their efficacies. Here, we have reviewed the currently available preclinical and clinical data in CRC treatment, with a focus on how the gut microbiome influences radio- and immunotherapy toxicity and efficacy and if these treatments could benefit from FMT.

Limnospira indica PCC 8005 Supplementation Prevents Pelvic Irradiation-Induced Dysbiosis but Not Acute Inflammation in Mice.

Pelvic irradiation-induced mucositis secondarily leads to dysbiosis, which seriously affects patients' quality of life after treatment. No safe and effective radioprotector or mitigator has yet been approved for clinical therapy. Here, we investigated the potential protective effects of fresh biomass of Limnospira indica PCC 8005 against ionizing irradiation-induced mucositis and dysbiosis in respect to benchmark probiotic Lacticaseibacillus rhamnosus GG ATCC 53103. For this, mice were supplemented daily before and after 12 Gy X-irradiation of the pelvis. Upon sacrifice, food supplements' efficacy was assessed for intestinal barrier protection, immunomodulation and changes in the microbiota composition. While both could not confer barrier protection or significant immunomodulatory effects, 16S microbial profiling revealed that L. indica PCC 8005 and L. rhamnosus GG could prevent pelvic irradiation-induced dysbiosis. Altogether, our data show that-besides benchmarked L. rhamnosus GG-L. indica PCC 8005 is an interesting candidate to further explore as a radiomitigator counteracting pelvic irradiation-induced dysbiosis in the presented in vivo irradiation-gut-microbiota platform.

Irradiation at Ultra-High (FLASH) Dose Rates Reduces Acute Normal Tissue Toxicity in the Mouse Gastrointestinal System.

PURPOSE: Preclinical studies using ultra-high dose rate (FLASH) irradiation have demonstrated reduced normal tissue toxicity compared with conventional dose rate (CONV) irradiation, although this finding is not universal. We investigated the effect of temporal pulse structure and average dose rate of FLASH compared with CONV irradiation on acute intestinal toxicity. MATERIALS AND METHODS: Whole abdomens of C3H mice were irradiated with a single fraction to various doses, using a 6 MeV electron linear accelerator with single pulse FLASH (dose rate = 2-6 × 106 Gy/s) or conventional (CONV; 0.25 Gy/s) irradiation. At 3.75 days postirradiation, fresh feces were collected for 16S rRNA sequencing to assess changes in the gut microbiota. A Swiss roll-based crypt assay was used to quantify acute damage to the intestinal crypts to determine how tissue toxicity was affected by the different temporal pulse structures of FLASH delivery. RESULTS: We found statistically significant improvements in crypt survival for mice irradiated with FLASH at doses between 7.5 and 12.5 Gy, with a dose modifying factor of 1.1 for FLASH (7.5 Gy, P < .01; 10 Gy, P < .05; 12.5 Gy, P < .01). This sparing effect was lost when the delivery time was increased, either by increasing the number of irradiation pulses or by prolonging the time between 2 successive pulses. Sparing was observed for average dose rates of ≥280 Gy/s. Fecal microbiome analysis showed that FLASH irradiation caused fewer changes to the microbiota than CONV irradiation. CONCLUSIONS: This study demonstrates that FLASH irradiation can spare mouse small intestinal crypts and reduce changes in gut microbiome composition compared with CONV irradiation. The higher the average dose rate, the larger the FLASH effect, which is also influenced by temporal pulse structure of the delivery.