Glycyrrhizin Protects γ-Irradiated Mice from Gut Bacteria-Associated Infectious Complications by Improving miR-222 -Associated Gas5 RNA Reduction in Macrophages of the Bacterial Translocation Site.

Gut bacteria-associated sepsis is a serious concern in patients with gastrointestinal acute radiation syndrome (GIARS). In our previous studies, gut bacteria-associated sepsis caused high mortality rates in mice exposed to 6-9 Gy of gamma-rays. IL-12(+) CD38(+) iNOS(+) M phi (M1M phi) located in the bacterial translocation site (mesenteric lymph nodes [MLNs]) of unirradiated mice were characterized as host defense antibacterial effector cells. However, cells isolated from the MLNs of GIARS mice were mostly CCL1(+)IL-10(+)LIGHT(+)miR-27a(+) M phi (M2bM phi, inhibitor cells for the M1M phi polarization). Reduced long noncoding RNA Gas5 and increased miR-222 expression in MLN-M phi influenced by the irradiation were shown to be associated with M2bM phi polarization. In this study, the mortality of mice exposed to 7 Gy of gamma-rays (7 Gy GIARS mice) was completely controlled after the administration of glycyrrhizin (GL), a major active ingredient in licorice root (Glycyrrhiza glabra). Bacterial translocation and subsequent sepsis were minimal in 7 Gy GIARS mice treated with GL. Increased Gas5 RNA level and decreased miR-222 expression were shown in MLN-M phi isolated from 7 Gy GIARS mice treated with GL, and these macrophages did not display any properties of M2bM phi. These results indicate that gut bacteria-associated sepsis in 7 Gy GIARS mice was controlled by the GL through the inhibition of M2bM phi polarization at the bacteria translocation site. Expression of Ccl1, a gene required for M2bM phi survival, is silenced in the MLNs of 7 Gy GIARS mice because of Gas5 RNA, which is increased in these cells after the suppression of miR-222 (a Gas5 RNA expression inhibitor) by the GL.