Faecal microbiota transplantation protects against radiation-induced toxicity

Ming Cui, Huiwen Xiao, Yuan Li, Lixin Zhou, Shuyi Zhao, Dan Luo, Qisheng Zheng, Jiali Dong, Yu Zhao, Xin Zhang, Junling Zhang, Lu Lu, Haichao Wang, Saijun Fan, Ming Cui, Huiwen Xiao, Yuan Li, Lixin Zhou, Shuyi Zhao, Dan Luo, Qisheng Zheng, Jiali Dong, Yu Zhao, Xin Zhang, Junling Zhang, Lu Lu, Haichao Wang, Saijun Fan

Abstract

Severe radiation exposure may cause acute radiation syndrome, a possibly fatal condition requiring effective therapy. Gut microbiota can be manipulated to fight against many diseases. We explored whether intestinal microbe transplantation could alleviate radiation-induced toxicity. High-throughput sequencing showed that gastrointestinal bacterial community composition differed between male and female mice and was associated with susceptibility to radiation toxicity. Faecal microbiota transplantation (FMT) increased the survival rate of irradiated animals, elevated peripheral white blood cell counts and improved gastrointestinal tract function and intestinal epithelial integrity in irradiated male and female mice. FMT preserved the intestinal bacterial composition and retained mRNA and long non-coding RNA expression profiles of host small intestines in a sex-specific fashion. Despite promoting angiogenesis, sex-matched FMT did not accelerate the proliferation of cancer cells in vivo FMT might serve as a therapeutic to mitigate radiation-induced toxicity and improve the prognosis of tumour patients after radiotherapy.

Keywords: faecal microbiota transplantation; gastrointestinal toxicity; gut microbiota; radiation syndrome; radiotherapy.

© 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Figures

Figure 1. The intestinal bacterial flora profile…
Figure 1. The intestinal bacterial flora profile is associated with radiosensitivity in a mouse model
  1. A, B

    The observed species number and Shannon diversity index of intestinal bacteria in male (A) and female (B) mice were examined by 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4 per group. Statistically significant differences are indicated: Wilcoxon rank sum test. The top and bottom boundaries of each box indicate the 75th and 25th quartile values, respectively, and lines within each box represent the 50th quartile (median) values. Ends of whiskers mark the lowest and highest diversity values in each instance.

  2. C, D

    The Shannon diversity index and β‐diversity of intestinal bacteria in male (C) and female (D) mice were examined by 16S high‐throughput sequencing after 6 weeks of antibiotics treatment, n = 4 per group. Statistically significant differences are indicated: Wilcoxon rank sum test. The top and bottom boundaries of each box indicate the 75th and 25th quartile values, respectively, and lines within each box represent the 50th quartile (median) values. Ends of whiskers mark the lowest and highest diversity values in each instance.

  3. E, F

    Kaplan–Meier survival analysis of saline‐treated, ampicillin‐treated, and streptomycin‐treated male (E) and female (F) mice after 6.5 Gy TBI were performed (aP < 0.05 by log‐rank test between antibiotic‐treated and saline‐treated groups; bP < 0.005 by log‐rank test between antibiotic‐treated and saline‐treated groups, n = 6 per group).

Figure 2. Gavage of faecal microbiota protects…
Figure 2. Gavage of faecal microbiota protects against radiation‐induced death and haematopoietic toxicity
  1. A

    The Shannon diversity index and β‐diversity of intestinal bacteria between male and female mice without irradiation were assessed by 16S high‐throughput sequencing, n = 4. Statistically significant differences are indicated: Student's t‐test. The top and bottom boundaries of each box indicate the 75th and 25th quartile values, respectively, and lines within each box represent the 50th quartile (median) values. Ends of whiskers mark the lowest and highest diversity values in each instance.

  2. B

    The relative abundances of the top 10 bacteria at the genus level in male and female mice were assessed using 16S high‐throughput sequencing, n = 4.

  3. C

    Scheme for radioprotection after TBI.

  4. D

    Male mice received 10 days of oral gavage with saline, male gut microbes, female gut microbes or a male/female gut microbe mixture after 6.5 Gy TBI, Kaplan–Meier survival analysis of the mice was performed. P < 0.005 by log‐rank test between the saline + TBI group and the male + TBI group, P < 0.05 by the log‐rank test between the saline + TBI group and the female + TBI group (or female/male + TBI group), n = 18 per group.

  5. E

    Male mice received 10 days of oral gavage with saline, male gut microbes, female gut microbes or a male/female gut microbe mixture after 6.5 Gy TBI, and the body weight was measured. Mean ± SD. Significant differences are shown relative to Saline + TBI group: **P < 0.01, ***P < 0.001; Student's t‐test, n = 18 per group.

  6. F, G

    Photographs (F) and volume (G) of dissected spleens from radiation‐exposed male mice, the spleens were obtained at day 15 after 6.5 Gy TBI. Mean ± SD. Significant differences are shown relative to Saline + TBI group: **P < 0.01; Student's t‐test, n = 6 in Saline group, n = 8 in experimental groups.

  7. H

    Scheme for faecal microbiota transplantation combined with bone marrow transplant after TBI.

  8. I

    Kaplan–Meier survival analysis of the irradiated mice treated with saline, FMT, BMT or FMT combined with BMT was performed. P < 0.005 by log‐rank test between FMT combined with BMT and other three groups, n = 12 per group.

Figure EV1. Gavage of faecal microbiota protects…
Figure EV1. Gavage of faecal microbiota protects against radiation‐induced death and hematopoietic toxicity
  1. A

    Female mice received 10 days of oral gavage with saline, male gut microbes, female gut microbes or male/female gut microbes mixture after 6.5 Gy TBI. Kaplan–Meier survival analysis of the mice was performed. n = 18, P < 0.05 by log‐rank test between saline + TBI group and female + TBI group.

  2. B

    Female mice received 10 days of oral gavage with saline, male gut microbes, female gut microbes or male/female gut microbes mixture after 6.5 Gy TBI, the body weight was measured. Significant differences are shown relative to Saline + TBI group: *P < 0.05, ***P < 0.001; Student's t‐test, n = 18 per group.

  3. C, D

    Photographs (C) and volume (D) of dissected spleens from radiation‐exposed female mice, the spleens were obtained at day 15 after 6.5 Gy TBI. Mean ± SD. Significant differences are shown relative to Saline + TBI group: **P < 0.01; Student's t‐test, n = 4 in Saline group, n = 6 in experimental groups.

  4. E, F

    WBC and HGB counts in PB were measured in irradiated male mice, the PB were obtained at day 15 after 6.5 Gy TBI. Mean ± SD. Significant differences are shown relative to the saline + TBI group: ***P < 0.005; Student's t‐test, n = 12 per group.

  5. G, H

    WBC and HGB counts in PB were measured in radiation‐exposed female mice, the PB were obtained at day 15 after 6.5 Gy TBI. Mean ± SD. Statistically significant differences are shown relative to the saline + TBI group: ***P < 0.005; Student's t‐test, n = 12 per group.

  6. I

    Kaplan–Meier survival analysis of the irradiated female mice treated with saline, FMT, BMT or FMT combined with BMT was performed. P < 0.005 by log‐rank test between FMT combined with BMT and other three groups, n = 12 per group.

Figure 3. FMT ameliorates GI tract function…
Figure 3. FMT ameliorates GI tract function and epithelial integrity after irradiation
Male mice were separated into two groups after 6.5 Gy gamma ray exposure, where one cohort was treated with saline as a control and the other was treated with sex‐matched FMT.
  1. A

    The morphology of the small intestine in the radiation‐induced mice treated with saline or sex‐matched FMT was shown by H&E, AB‐PAS and PAS staining; the small intestine tissues were obtained at day 21 after TBI. The arrows point to the mucus layer or goblet cells.

  2. B, C

    Faecal pellet counts removed from cage bedding on 3 day from representative cages is shown. Mean ± SD, n = 6 mice per treatment, ***P < 0.001 by Student's t‐test between Saline + TBI and Male + TBI group.

  3. D

    The FITC–dextran in peripheral blood from saline‐treated and sex‐matched FMT mice was assessed at day 21 after irradiation exposure. Mean ± SD. Significant differences are indicated: **P < 0.01; Student's t‐test, n = 6 per group.

  4. E–I

    The expression levels of Muc2, Glut1, Pgk1, MDR1 and TFF3 were examined in small intestine tissues from saline‐treated and sex‐matched FMT mice by quantitative PCR; the small intestine tissues were obtained at day 21 after TBI. Mean ± SD. Significant differences are indicated: **P < 0.01; Student's t‐test, n = 12 per group.

Figure EV2. Faecal microbiota transplant ameliorates GI…
Figure EV2. Faecal microbiota transplant ameliorates GI tract function and epithelial integrity after irradiation
Female mice were separated into two groups after 6.5 Gy gamma ray exposure, one cohort was treated with saline as control, and the other was treated with sex‐matched FMT.
  1. A

    The morphology of small intestine in radiation‐induced mice treated with saline or sex‐matched FMT is shown by H&E, AB‐PAS and PAS staining, the small intestine tissues were obtained at day 21 after TBI. The arrows point to the mucus layer or goblet cells.

  2. B, C

    Faecal pellet counts removed from cage bedding per 3 day from representative cages. Mean ± SD, n = 6 mice per treatment. ***P < 0.001 by Student's t‐test between Saline + TBI and Female + TBI group.

  3. D

    The FITC–dextran in peripheral blood from saline‐treated and sex‐matched FMT mice was assessed at day 21 after irradiation exposure. Mean ± SD. Significant differences are indicated: *P < 0.05, **P < 0.01; Student's t‐test, n = 6 per group.

  4. E–I

    The expression levels of Muc2, Glut1, Pgk1, MDR1 and TFF3 were examined in saline‐treated and sex‐matched FMT mice by quantitative PCR, the small intestine tissues were obtained at day 21 after TBI. Mean ± SD. Statistically significant differences are indicated: **P < 0.01; Student's t‐test, n = 12 per group.

Figure 4. FMT alters the gut bacterial…
Figure 4. FMT alters the gut bacterial composition profile after irradiation
  1. A, B

    The alteration of intestinal bacterial patterns at the genus level in saline‐treated (A) and sex‐matched FMT (B) male mice was assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4. The heat map is colour‐based on row Z‐scores. The mice with the highest and lowest bacterial level are in red and blue, respectively.

  2. C, D

    The relative abundances of the top 10 bacteria at the genus level in saline‐treated (C) and sex‐matched FMT (D) male mice were assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4.

  3. E, F

    The alterations of intestinal bacterial patterns at the genus level in saline‐treated (E) and sex‐matched FMT (F) female mice were assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4. The heat map is colour‐based on row Z‐scores. The mice with the highest and lowest bacterial level are in red and blue, respectively.

  4. G, H

    The relative abundances of the top 10 bacteria at the genus level in saline‐treated (G) and sex‐matched FMT (H) female mice were assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4.

Figure EV3. Faecal microbiota transplantation alters gut…
Figure EV3. Faecal microbiota transplantation alters gut bacterial composition profile after irradiation
  1. A, B

    The alteration of intestinal bacterial patterns at the genus level in sex‐mismatched FMT (A) and sex‐mixed FMT (B) male mice was assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4. The heat map is colour‐based on row Z‐scores. The mice with the highest and lowest bacterial level are in red and blue, respectively.

  2. C, D

    The relative abundance of top 10 bacteria at the genus level in sex‐mismatched FMT (C) and sex‐mixed FMT (D) male mice was assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4.

  3. E, F

    The alteration of intestinal bacterial patterns at the genus level in sex‐mismatched FMT (E) and sex‐mixed FMT (F) female mice was assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4. The heat map is colour‐based on row Z‐scores. The mice with highest and lowest bacterial level are in red and blue, respectively.

  4. G, H

    The relative abundance of top 10 bacteria at the genus level in sex‐mismatched FMT (G) and sex‐mixed FMT (H) female mice was assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10, n = 4.

Figure 5. FMT changes gut bacterial community…
Figure 5. FMT changes gut bacterial community structure after irradiation
Male and female mice were separated into two groups after 6.5 Gy gamma ray exposure, where one cohort was treated with saline as control and the other was treated with sex‐matched FMT.
  1. A, B

    Principal component and β‐diversity analysis were used to measure the shift of the intestinal bacterial composition profile in saline‐treated (A) and sex‐matched FMT (B) male mice after irradiation at days 5 and 10, n = 4. Statistically significant differences are indicated: Wilcoxon rank sum test. The top and bottom boundaries of each box indicate the 75th and 25th quartile values, respectively, and lines within each box represent the 50th quartile (median) values. Ends of whiskers mark the lowest and highest diversity values in each instance.

  2. C, D

    Principal component and β‐diversity analysis were used to measure the shift of the intestinal bacterial composition structure in saline‐treated (C) and sex‐matched FMT (D) female mice after irradiation at days 5 and 10, n = 4. Statistically significant differences are indicated: Wilcoxon rank sum test. The top and bottom boundaries of each box indicate the 75th and 25th quartile values, respectively, and lines within each box represent the 50th quartile (median) values. Ends of whiskers mark the lowest and highest diversity values in each instance.

  3. E, F

    The relative abundances of enteric bacteria at the phylum level in saline‐treated (E) and sex‐matched FMT (F) from male mice were assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10.

  4. G, H

    The relative abundances of enteric bacteria at the phylum level in saline‐treated (G) and sex‐matched FMT (H) from female mice were assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10.

Figure EV4. FMT shifts gut bacterial composition…
Figure EV4. FMT shifts gut bacterial composition profile after irradiation
  1. A, B

    Principal component and β‐diversity analysis were used to measure the shift of intestinal bacterial composition profile in sex‐mismatched FMT (A) and sex‐mixed FMT (B) male mice after irradiation at days 5 and 10, n = 4. Statistically significant differences are indicated: Wilcoxon rank sum test. The top and bottom boundaries of each box indicate the 75th and 25th quartile values, respectively, and lines within each box represent the 50th quartile (median) values. Ends of whiskers mark the lowest and highest diversity values in each instance.

  2. C, D

    Principal component and β‐diversity analysis were used to measure the shift of intestinal bacterial composition structure in sex‐mismatched FMT (C) and sex‐mixed FMT (D) female mice after irradiation at days 5 and 10, n = 4. Statistically significant differences are indicated: Wilcoxon rank sum test. The top and bottom boundaries of each box indicate the 75th and 25th quartile values, respectively, and lines within each box represent the 50th quartile (median) values. Ends of whiskers mark the lowest and highest diversity values in each instance.

  3. E, F

    The relative abundance of enteric bacteria at the phylum level in sex‐mismatched FMT (E) and sex‐mixed FMT (F) from male mice was assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10.

  4. G, H

    The relative abundance of enteric bacteria at the phylum level in sex‐mismatched FMT (G) and sex‐mixed FMT (H) from female mice was assessed using 16S high‐throughput sequencing after irradiation at days 5 and 10.

Figure 6. FMT retains the gene expression…
Figure 6. FMT retains the gene expression profile of the small intestine after irradiation
Male and female mice were separated into two groups after 6.5 Gy gamma ray exposure, where one cohort was treated with saline as control and the other was treated with sex‐matched FMT. Twenty‐one days after irradiation, the mice were euthanized, and the small intestine tissues were excised and microarray analysis was performed.
  1. A

    Significantly enriched GO terms (top 30) induced by sex‐matched FMT in male mice. AIRBSRIRBISD, adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains.

  2. B

    Significantly enriched GO terms (top 30) induced by sex‐matched FMT in female mice.

  3. C, D

    Heat map of genes significantly up‐ and down‐regulated (red and green, respectively) in small intestine tissue from sex‐matched FMT male mice compared with those of controls. The genes were associated with immunity (C) and metabolism (D), and each row represents a single gene.

  4. E, F

    Heat map of genes significantly up‐ and down‐regulated (red and green, respectively) in small intestine tissue from sex‐matched FMT female mice compared with those of controls. The genes were associated with metabolism (E) and immunity (F), and each row represents a single gene.

Figure 7. FMT enhances angiogenesis without accelerating…
Figure 7. FMT enhances angiogenesis without accelerating tumour growth

  1. The level of F8 was assessed in small intestine tissue by immunohistochemistry in saline‐treated and sex‐matched FMT male mice (or sex‐matched FMT female mice).

  2. The expression level of Vegf in saline‐treated and sex‐matched FMT male mice (or sex‐matched FMT female mice) was examined by quantitative PCR. Mean ± SD. Significant differences are indicated: *P < 0.05, **P < 0.01; Student's t‐test, n = 12 per group.

  3. Photographs of dissected tumours from saline‐treated or sex‐matched FMT C57BL/6 mice transplanted with HT29.

  4. The weight of tumours from experimental groups of C57BL/6 mice. Mean ± SD. Significant differences are indicated: none significant; Student's t‐test, n = 5 per group.

  5. Photographs of dissected tumours from saline‐treated or sex‐matched FMT C57BL/6 mice transplanted with A549.

  6. The weight of tumours from experimental groups of C57BL/6 mice. Mean ± SD. Significant differences are indicated: none significant; Student's t‐test, n = 5 per group.

Figure EV5. Gavage of gut microbiota enhances…
Figure EV5. Gavage of gut microbiota enhances angiogenesis without accelerating tumour growth
  1. A, B

    Photographs of tumours transplanted into female (A) and male (B) C57BL/6 mice subcutaneously.

  2. C, D

    The body weight curve of male (C) and female (D) C57BL/6 mice transplanted with HT29 subcutaneously. Mean ± SD. None significant; Student's t‐test, n = 5 per group.

  3. E, F

    The body weight curve of male and female C57BL/6 mice transplanted with A549 subcutaneously. Mean ± SD. Statistically significant differences are indicated: Student's t‐test. None significant; Student's t‐test, n = 5 per group.

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Source: PubMed

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