Bacterial Supplements Attenuate Pelvic Irradiation-Induced Brain Metabolic Disruptions via the Gut-Brain Axis: A Multi-Omics Investigation

Abstract

Recent advancements in cancer treatments have increased patient survival rates but also led to treatment-related side effects, negatively impacting the quality of life for cancer survivors. Research has highlighted the crucial role of gut microbiota in overall health, including cognition and neurodegenerative disorders. Cancer patients receiving pelvic radiation often experience gut dysbiosis and this may induce changes in brain through the bi-directional connection between the gut microbiota and the brain, known as the microbiota-gut-brain axis. Bacterial supplements intended to enhance health, whether consumed orally or applied topically. However, the mechanism of bacterial supplements to mitigate pelvic radiation-induced metabolomic alterations is not understood. To investigate this, we employed a multi-omics approach to elucidate how these supplements might mitigate radiation-induced metabolomic changes in the rat brain. A single 6 Gy dose of pelvic radiation was administered to 3-4-month-old Sprague Dawley rats and formulated bacterial supplements were given accordingly. Faecal bacterial sequencing and brain metabolomics performed to identify the changes in the gut microbiota and brain metabolomic analysis to check the altered brain metabolites post pelvic radiation. High-throughput 16S rRNA sequencing revealed significant shifts in bacterial composition, with reduced diversity in the radiation group compared to controls, which was restored in the supplementation groups. Notably, the dominant genera in the radiation group included Methanobrevibacter, while Parasutterella and Brachyspira were prevalent in the supplementation cohorts. Untargeted metabolomic analysis identified 2,554 annotated metabolites, with 56 showing significant differences across groups. Principal Component Analysis demonstrated distinct metabolomic profiles between irradiated and control groups, with specific metabolomic pathways like retinol and glycerophospholipid metabolism altered by irradiation. Bacterial supplementation significantly attenuated these metabolomic disruptions. Therefore, bacterial supplementation could be a promising approach to addressing radiation-induced metabolomic reprogramming in the brains through gut dysbiosis in patients undergoing pelvic radiotherapy, enhancing overall well-being.