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DOI: 10.1101/2023.05.21.541625

Pelvic irradiation induces behavioral and neuronal damage through gut dysbiosis in a rat model

B. S.Venkidesh R. K. Narasimhamurthy A. Jnana ...+3 K. D. Mumbrekar
Background: Pelvic radiotherapy is the endorsed course of treatment for pelvic malignancies, which frequently cover pelvic primary tumor lesions as well as non-cancerous lymphatic drainage sites in the pelvic area. As a result, pelvic irradiation may indiscriminately cause harm to healthy tissues and organs in the pelvic area in individuals undergoing treatment. Some studies suggest that gut microbial dysbiosis can be correlated with the incidence of radiation-induced toxicities in cancer patients. Since, the consequences were earlier thought to be solely due to the targeted or non-targeted effect of radiation, the role of gut microbiota in the non-targeted effects of radiation and the mechanistic role of the gut-brain axis in the pelvic irradiation scenario is not well explored. Hence, the current study was carried out to explore implication of gut dysbiosis in behavioral and neuronal changes induced by pelvic irradiation. Materials & Methods: 3-4-month-old Sprague Dawley rats were given a single dose of 6 Gy pelvic irradiation. Fecal samples of control and treated mice were collected at different timepoints to assess microbial abundance and diversity using 16S rRNA-based metagenomic sequencing. Behavioral analysis, histological analysis of intestine, brain and gene expression analysis of brain hippocampus was performed to ascertain the indirect impact of microbial dysbiosis on cognition. Results: Following pelvic irradiation, significant microbial dysbiosis and behavioral alterations were observed with distinct changes in the microbial diversity and a significant decline in the locomotor effect and anxiety level at each time point following radiation. Histological analysis revealed a significant reduction in villous distortion as well as a significant decrease in neuronal cells, matured neurons, and an increase in reactive astrocytes, suggesting that pelvic irradiation promotes neuroinflammation. Gene expression analysis revealed a significant reduction in neural plasticity. Altogether, this study demonstrated that gut dysbiosis caused by pelvic irradiation alters behavior, intestinal morphology, integrity, and brain neuronal maturation, as well as lowers the levels of neural plasticity expression. Conclusion: Current study provides evidence for the influence of gut dysbiosis on pelvic irradiation induced cognitive impairment in a rat model.