Proton FLASH Exposure Preserves Gut Commensal Microbiomes and Spares Intestinal Stem Cells

Area of Science:

• Radiation Oncology
• Gastroenterology
• Microbiome Research

Background:

• Proton FLASH radiotherapy shows promise for sparing normal tissues.
• The effects of Proton FLASH on intestinal stem cells (ISCs) and the gut microbiome are not well understood.
• Gut microbiome composition influences ISC radiosensitivity.

Purpose of the Study:

• To investigate the impact of Proton FLASH radiotherapy on ISCs and the gut microbiome.
• To compare Proton FLASH with conventional dose rate proton therapy in a mouse model.
• To elucidate the mechanisms behind Proton FLASH-mediated tissue sparing.

Main Methods:

• Mouse model of abdominal irradiation.
• Proton FLASH and conventional dose rate proton irradiation.
• Single-cell RNA sequencing (scRNA-seq) of ISCs.
• Gut microbiome analysis (α and β-diversity).
• Fecal microbiota transplantation (FMT).

Main Results:

• Proton FLASH improved survival and reduced crypt-villus damage compared to conventional dose rate.
• scRNA-seq identified spared Lgr5+ CBCs and revSC populations under Proton FLASH.
• Proton FLASH modulated gut microbiota composition, increasing beneficial species like Alistipes and Akkermansia.
• FMT experiments confirmed the microbiome's role in Proton FLASH-mediated protection.

Conclusions:

• Proton FLASH radiotherapy spares distinct intestinal stem cell populations.
• The gut microbiome plays a critical role in the protective effects of Proton FLASH on the intestinal epithelium.
• Proton FLASH offers a promising strategy for radiotherapy with reduced normal tissue toxicity.