Probiotic Consortia and their Metabolites Protect Intestine Against Radiation Injury by Improving Intestinal Epithelial Homeostasis

Abstract

The intestine is a highly radiosensitive tissue that is susceptible to structural and functional damage due to systemic as well as localized radiation exposure. Unfortunately, no therapeutic agents are available at present to manage radiation-induced intestinal injuries (RIII). Probiotics, especially Lactobacillus or Bifidobacterium, are orally taken as food supplements or microbial drugs by patients with gastrointestinal disorders due to their safety, efficacy, and power to restore the gut microenvironment. Our results demonstrate that probiotic consortia and their metabolites could exert protective roles in the RIII mouse model by restoring the structure of the gut microbiota and regulating redox imbalance. Moreover, the effect of probiotic consortia is better than that of any single probiotic strain. Male C57BL/6J mice were treated with 13 Gy of whole abdominal irradiation (WAI). Probiotics were administered by gavage before (once a day for 30 days) WAI. The survival and body weight were recorded, while the severity of RIII was evaluated by HE staining, immunohistochemistry (IHC) and TUNEL assay of gut tissues. Meanwhile, stool samples were obtained 3.5 d after irradiation. Gut microbiome were measured by 16S rRNA sequencing, and metabolites were detected by LC-MS analysis. For sterile fecal filtrate (SFF), the supernatants were collected and passed through 70 and 0.2μm filters. Compared to the control, probiotic consortia (Lactobacillus plantarum, Bifidobacterium longum, Lactobacillus paracasei) treatment significantly increased survival rates by 50% (P<0.05) and improved clinical scores of mice after WAI. HE staining showed that probiotics mitigated RIII, as reflected by the dramatic attenuation of crypt-villus architecture destruction. IHC results showed that probiotic consortia treatment markedly increased the Lgr5+ cells, Paneth cells, and Ki67+ cells (P<0.001) per crypt, indicating that probiotics promoted the proliferation and differentiation of ISCs after WAI. Consistent with the H&E staining, the level of CD4/CD8 was increased by the probiotic consortia compared with that of the control group. The probiotic consortia modulated the structure of the gut microbiota and metabolites in the RIII mouse model. To further investigate the impact of metabolites on RIII, crude probiotic fermentation metabolites were administered to the RIII mouse model. Specifically, mice fed the mixed-metabolite daily for 7 days before IR had significantly more Lgr5+ and Ki67+cells in the SI crypt than mice of control. Moreover, treatment with mixed metabolites resulted in insignificant changes in SOD, MDA, GSH and T-AOC activity compared to the control group in intestinal tissues. In the present study, we demonstrate that probiotic consortia and their metabolites treatment attenuate RIII by modulating the structure and composition of the gut microbiota and regulating redox imbalance.