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. 2021 Oct 25:11:717636.
doi: 10.3389/fcimb.2021.717636. eCollection 2021.

V体育平台登录 - Dysbiosis of Gut Microbiota Is Associated With the Progression of Radiation-Induced Intestinal Injury and Is Alleviated by Oral Compound Probiotics in Mouse Model

Tian-Shu Zhao  1   2 , Li-Wei Xie  1   2 , Shang Cai  1   2 , Jia-Yu Xu  1   2 , Hao Zhou  3 , Lin-Feng Tang  3 , Chao Yang  4 , Shuguang Fang  5 , Ming Li  3 , Ye Tian  1   2
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Dysbiosis of Gut Microbiota Is Associated With the Progression of Radiation-Induced Intestinal Injury and Is Alleviated by Oral Compound Probiotics in Mouse Model (V体育平台登录)

Tian-Shu Zhao et al. Front Cell Infect Microbiol. .

"VSports手机版" Abstract

The acute radiation-induced intestinal injury (RIII) has raised much concerns and is influenced by non-cytocidal radiation effects including the perturbations in gut microbiota. Although a number of studies have reported alteration in gut microbiota following radiation, little is known about its dynamic variation in the progression of acute RIII. In this study, mouse model were treated with total body irradiation (TBI) of 0, 4, 8 and 12 Gy, and the intestinal tissues and fecal samples were collected at 6 h, 3. 5 d and 7 d post radiation. We found that the intestinal injuries were manifested in a radiation dose-dependent manner. Results from 16S rRNA gene sequencing demonstrated that the diversity of gut microbiota was not significantly affected at the prodromal stage of acute RIII, after 6 h of radiation. At the critical stage of acute RIII, after 3. 5 d of radiation, the composition of gut microbiota was correlated with the radiation dose VSports手机版. The Pearson's correlation analysis showed that the relative abundances of phylum Proteobacteria, genera Escherichia-Shigella and Eubacterium xylanophilum_group, and species Lactobacillus murinus exhibited linear correlations with radiation dose. At the recovery stage of acute RIII, after 7 d of radiation, the diversity of gut microbiota decreased as a whole, among which the relative abundance of phyla Proteobacteria and Bacteroides increased, while that of phylum Tenericutes and genus Roseburia decreased. The intra-gastric administration of compound probiotics for 14 days improved the survival duration of mice exposed to 9 Gy TBI, alleviated the intestinal epithelial injury and partially restored the diversity of gut microbiota. Our findings suggest that acute RIII is accompanied by the dysbiosis of gut microbiota, including its decreased diversity, reduced abundance of beneficial bacteria and increased abundance of pathogens. The gut microbiota cannot be used as sensitive biomarkers at the prodromal stage in acute RIII, but are potential biomarkers at the critical stage of acute RIII. The dysbiosis is persistent until the recovery stage of acute RIII, and interventions are needed to restore it. The administration of probiotics is an effective strategy to protect against acute RIII and subsequent dysbiosis. .

Keywords: biomarker; dysbiosis; intestinal injury; ionizing radiation; probiotics V体育安卓版. .

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Conflict of interest statement

Author SF was employed by company Wecare Probiotics (Suzhou) Co VSports最新版本. , Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Effects of different doses of radiation on survival and intestinal injuries of C57 mice. (A) Kaplan-Meier survival analysis of mice after 0, 4, 8 and 12 Gy TBI. (B) Body weights of radiated mice in each group after 0, 4, 8 and 12 Gy TBI. (C) Representative H&E stained images of intestinal tissues harvested at 6 h, 3.5 d and 7 d following radiation. (D–F) Bar graph of the villus height determined from panel (C) (n = 6/group; * indicates P < 0.05; **** indicates P < 0.001).
Figure 2
Figure 2
Injury degree of small intestine was dependent with radiation doses in mouse models. (A) The representative IHC images for the expression of Ki67 in small intestine from radiated mice were compared with that from the control mice at 3.5 d post radiation. The number of (B) Ki67 positive cells in each crypt and (C) Ki67 positive crypts per circumference determined from Ki67-immunostained sections of small intestines. At least 30 well-oriented crypts per mouse were counted. The crypt, having more than 10 Ki67 positive cells, was identified as a Ki67 positive crypt. (D) Representative images from intestine at 6 h post radiation were shown for apoptotic cells determined by TUNEL assay. (E) Number of apoptotic cells in each crypt determined from TUNEL stained sections of small intestines. (n = 6/group; * indicates P < 0.05; *** indicates P < 0.001; **** indicates P < 0.0001).
Figure 3
Figure 3
Diversity of gut microbiota of mice following 0, 4, 8 and 12 Gy TBI changed with the fecal collection time in Chao1 index and PCoA analysis. The (A) Chao1 and (B) PCoA of microbial communities from the control mice at 6 h, 3.5 d and 7 d. The (C, E, G) for Chao1 indices and (D, F, H) for the PCoA of gut microbiota from 4, 8 and 12 Gy radiated mice at 6 h, 3.5 d and 7 d (n = 6/group; * indicates P < 0.05; ** indicates P < 0.01); ns indicates no significance.
Figure 4
Figure 4
Effects of different doses of radiation on the bacterial diversity in alpha diversity analysis are shown (within-sample diversity). (A, C, E) Chao1 indices and (B, D, F) Shannon indices of the microbial alpha diversity from control and radiated C57 mice at 6 h, 3.5 d and 7 d after exposure to TBI doses of 4, 8 and 12 Gy. (n = 6/group; * indicates P < 0.05; ** indicates P < 0.01); ns indicates no significance.
Figure 5
Figure 5
Effects of different doses of radiation on gut microbiota in beta diversity analysis are shown (between-sample diversity). (A, C, E) UPGMA tree and (B, D, F) PCoA of the gut microbiota from control and radiated C57 mice at 6 h, 3.5 d and 7 d after exposure to TBI doses of 4, 8 and 12 Gy.
Figure 6
Figure 6
Bacterial markers associated with radiation doses at 3.5 d post radiation. (A, B) LEfSe analysis of key taxa, showing differences in the composition of gut microbiota among mice radiated with different doses. The characteristic taxonomies having LDA scores higher than 3.5 were selected and presented. Pearson correlation revealed that the relative abundance of (C) Proteobacteria, (D) Escherichia-Shigella, (E) Eubacterium xylanophilum_group, and (F) Lactobacillus murinus had the linear correlation with different radiation doses at 3.5 d post radiation. (G) Top 30 most abundant genera at 3.5 d post radiation were clustered by Spearman’s correlation distance. Three poly-microbial clusters with high covariance (intra cluster mean Spearman’s ρ > 0.5) and LDA scores of higher than 3.5 are presented in a heat map. (n = 6/group; * indicates P < 0.05; ** indicates P < 0.01; *** indicates P < 0.001).
Figure 7
Figure 7
Patterns of gut microbiota after pretreatment with probiotics for 14 days in mouse model. The richness and composition of gut microbiota were analyzed by (A) Chao1 index and (B) PCoA. (C, D) Differentially abundant bacteria between Control (red) and probiotics pretreatment group (green) are presented in a histogram of LDA scores using LEfSe. (E) The relative abundance of differentially abundant bacteria taxa in gut microbiota between groups after pretreatment with probiotics. (n = 5/group; ** indicates P < 0.01); ns indicates no significance.
Figure 8
Figure 8
Compound probiotics increased the survival time and reduced the weight loss of radiated mice. (A) Experimental schedule for the induction of gut injuries by radiation and intervention with probiotics. C57 BL/6J mice received oral gavage of PBS or probiotics for 10 consecutive days before 9 Gy TBI and 4 consecutive days after TBI. (B) Kaplan-Meier survival analysis of mice after 9 Gy TBI. (C) Body weights of radiated mice in each group after 9 Gy TBI (n = 8/group; *indicates P < 0.05; *** indicates P < 0.001).
Figure 9
Figure 9
Compound probiotics alleviated the intestinal epithelium injury in RIII. Intestinal tissues were harvested at 4 d following radiation. Representative images from histological staining by (A) H&E, (B) PAS and (C) IHC for Ki67. Histogram showing the (D) villus height, (E) number of Goblet cells per villi, (F) numbers of Ki67 positive crypts per circumference and (G) Ki67 positive cells in each crypt. (n = 5/group; *** indicates P < 0.001; **** indicates P < 0.0001).
Figure 10
Figure 10
Compound probiotics restored the diversity and composition of gut microbiota in radiated mice. The fecal samples were harvested at 4 d following IR. (A) Chao1 index in alpha diversity analysis and (B) PCoA in beta diversity analysis of gut microbiota in each group are shown. The relative abundance of (C) Proteobacteria, (D) Enterobacteriaceae, (E) Escherichia-Shigella, (F) Prevotellaceae NK3B31, (G) Lachinospiraceae and (H) Lachinospiraceae NK4A136 in each groups. (n = 5/group; * indicates P < 0.05; ** indicates P < 0.01; *** indicates P < 0.001); ns indicates no significance.
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