Abstract
Acute radiation injury caused by high-dose radiation exposure severely impedes the application of radiotherapy in cancer management. To deeply understand the side effects of radiation on intestinal tract, an irradiation murine model was applied and evaluated. C57BL/6 mice were given 4 Gy non-myeloablative irradiation, 8 Gy myeloablative irradiation and non-irradiation (control), respectively. Results demonstrated that the 8 Gy myeloablative irradiations significantly damaged the gut barrier along with decreasing MECA32 and ZO-1. However, a slight increase in MECA32 and ZO-1 was detected in the 4 Gy non-myeloablative irradiations treatment from day 5 to day 10. Further, the irradiations affected the expression of P38 and JNK mitogen-activated protein kinase (MAPK) but not ERK1/2 MAPK signal pathway. Moreover, irradiation had adverse effects on hematopoietic system, altered the numbers and percentages of intestinal inflammatory cells. The IL-17/AhR had big increase in the gut of 4 Gy irradiation mice at day 10 compared with other groups. Both 8 Gy myeloablative and 4 Gy non-myeloablative irradiation disturbed the levels of short-chain fatty acids (SCFAs) in intestine. Meanwhile, high dosage of irradiation decreased the intestinal bacterial diversity and altered the community composition. Importantly, the fatty acids generating bacteria Bacteroidaceae and Ruminococcaceae played key roles in community distribution and SCFAs metabolism after irradiation. Collectively, the irradiation induced gut barrier damage with dosages dependent that led to the decreased p38 MAPK and increased JNK MAPK, unbalanced the mononuclear cells (MNCs) of gut, disturbed intestinal bacterial community and SCFAs level.
Highlights
Malignant tumors have become the second leading cause of deaths worldwide and pose a serious threat to public health
Myeloablative irradiations induce the destruction of gut epithelial barrier To establish the Total body irradiation (TBI) mice model, C57BL/6 mice were treated with 4 Gy non-myeloablative TBI, 8 Gy myeloablative TBI and unirradiated treatment (CTR), respectively
The mRNA levels of ZO-1 and MECA32 (Figure 1B) showed a similar trend as the protein levels (Figure 1A). These results indicated that low dosage of irradiation induced mild gut injury but can be rescued in a short time (10 days in the study), this response was confirmed by the increasing ZO-1 in epithelial cells and MECA32 in vascular endothelial cells
Summary
Malignant tumors have become the second leading cause of deaths worldwide and pose a serious threat to public health. There are at least 50% malignant tumor patients treated by radiotherapy, 25% of which are able to survive [1]. Radiotherapy becomes an indispensable treatment for the majority of malignant tumors [1,2]. Acute radiation injury caused by high-dose radiation exposure severely limits the widespread application of radiotherapy because of the indiscriminate harm to normal tissues and organs [3,4]. Hematopoietic stem cell transplantation is recognized as a fundamental solution for hematological malignant tumor [7,8]. Total body irradiation (TBI) is used in humans mostly for the treatment of acute lymphatic leukemia as conditioning of transplant. Exposure to overdose of irradiation will limit the proliferation of crypt epithelial cells, impact the regeneration of villi epithelial cells, and further destroy
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