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Sexual Dimorphism of Gut Microbiota Dictates Therapeutics Efficacy of Radiation Injuries

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Sexual Dimorphism of Gut Microbiota Dictates Therapeutics Efficacy of Radiation Injuries

Ming Cui et al. Adv Sci (Weinh).

Abstract

Accidental or iatrogenic ionizing radiation exposure precipitates acute and chronic radiation injuries. The traditional paradigm of mitigating radiotherapy-associated adverse side effects has ignored the gender-specific dimorphism of patients' divergent responses. Here, the effects of sexual dimorphism on curative efficiencies of therapeutic agents is examined in murine models of irradiation injury. Oral gavage of simvastatin ameliorates radiation-induced hematopoietic injury and gastrointestinal tract dysfunction in male mice, but adversely deteriorates these radiation syndromes in female animals. In a sharp contrast, feeding animals with high-fat diet (HFD) elicites explicitly contrary results. High-throughput sequencing of microbial 16S rRNA, host miRNA, and mRNA shows that simvastatin or HFD administration preventes radiation-altered enteric bacterial taxonomic structure, preserves miRNA expression profile, and reprogrammes the spectrum of mRNA expression in small intestines of male or female mice, respectively. Notably, faecal microbiota transplantation of gut microbes from opposite sexual donors abrogates the curative effects of simvastatin or HFD in respective genders of animals. Together, these findings demonstrate that curative efficiencies of therapeutic strategies mitigating radiation toxicity might be dependent on the gender of patients, thus simvastatin or HFD might be specifically useful for fighting against radiation toxicity in a sex-dependent fashion partly based on sex-distinct gut microbiota composition in preclinical settings.

Keywords: adverse side effects; gut microbiota; radiotherapy; sexual dimorphism.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Sexual distinction impacts therapeutic effects toward radiation‐caused toxicity. A,B) Kaplan–Meier analysis A) and body weight measurement B) of male mice in the three groups after 7 Gy TBI, n = 30 per group; P < 0.05 by log‐rank test between simvastatin‐treated group and control (A); *P < 0.05 by Student's t‐test between simvastatin‐treated/HFD group and control (B). C,D) Kaplan–Meier analysis C) and body weight measurement D) of female mice in the three groups after 7 Gy TBI, n = 30 per group; P < 0.05 by log‐rank test between HFD group and control (C); *P < 0.05 by Student's t‐test between simvastatin‐treated/HFD group and control (D). E,F) Body weight was compared among three group mice of male E) and female F) after 12 Gy TAI, n = 24 per group; *P < 0.05 by Student's t‐test between simvastatin‐treated/HFD group and control. G,H) Kaplan‐Meier analysis of male G) and female H) mice treated with atorvastatin and rosuvastatin after 7 Gy TBI, n = 24 per group.
Figure 2
Figure 2
Simvastatin or HFD ameliorates radiation‐associated hematopoietic syndrome of male or female mice. A,B) Volume of dissected thymuses A) and Photographs of spleens B) from male mice in the four groups, the thymuses and spleens were obtained at day 21 after 4 Gy TBI. Mean ± SD. Significant differences are indicated: *P < 0.05, ***P < 0.005 by Student's t‐test between each two cohort, n = 18 per group. C,D) Volume of dissected thymuses C) and photographs of spleens D) from female mice in the four groups, the thymuses and spleens were obtained at day 21 after 4 Gy TBI. Mean ± SD. Significant differences are indicated: *P < 0.05, ***P < 0.005 by Student's t‐test between each two cohort, n = 18 per group. E,F) The levels of IL‐6 in PB of male E) and female F) were examined. Significant differences are indicated: *P < 0.05, **P < 0.01 by Student's t‐test between each two cohort, n = 18 per group. G,H) The levels of MDA in PB of male G) and female H) were examined. Significant differences are indicated: *P < 0.05, **P < 0.01, ***P < 0.005 by Student's t‐test between each two cohort, n = 18 per group.
Figure 3
Figure 3
Rehabilitation efficacy of simvastatin and HFD toward radiation‐induced gastrointestinal toxicity relates to sexual dimorphism. Male and Female mice were exposed to 12 Gy total abdominal irradiation, the colon and small intestine tissues were obtained at day 21, n = 24 per group. A,B) Photographs of dissected colon from male A) and female B) mice in the four groups. C,D) The morphology of the small intestine form male C) and female D) mice was shown by H&E and PAS staining. The black arrows point to the goblet cells. E,F) The levels of LCN2 in fecal pellets from male E) and female F) mice were examined by ELISA. Significant differences are indicated: *P < 0.05, **P < 0.01, ***P < 0.005 by Student's t‐test between each two cohort. G,H) The expression levels of Glut1 are examined in small intestine tissues from male G) and female H) mice by quantitative PCR. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort. I,J) The levels of MDA were assessed in small intestine tissue from male I) and female J) mice. Significant differences are indicated: *P < 0.05, **P < 0.01, ***P < 0.005 by Student's t‐test between each two cohort. K,L) The levels of FITC‐dextran in PB from male K) and female L) mice were assessed. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort.
Figure 4
Figure 4
Oral gavage of simvastatin and HFD educate radiation‐shifted intestinal bacterial structure at day 7 after TAI based on the gender of animal. For box plot, 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. A,B) The observed species number A) and Chao1 diversity index B) of intestinal bacteria in male mice was examined by 16S rRNA high‐throughput sequencing after 7 d of TAI exposure. Significant differences are indicated: Wilcoxon rank sum test. n = 5 (control group) or 6 (irradiated groups). C,D) The observed species number C) and Chao1 diversity index D) of intestinal bacteria in female mice was examined by 16S rRNA high‐throughput sequencing after 7 d of TAI exposure. Significant differences are indicated: Wilcoxon rank sum test. n = 5 (control group) or 6 (irradiated groups). E,F) Principle coordinate analysis (PCoA) were performed to assess the shift in intestinal bacterial composition profile from male E) and female F) mice after irradiation at day 7. n = 5 (control group) or 6 (irradiated groups). G,H) The β diversity of intestinal bacteria was compared by weighted unifrac analysis. Significant differences are indicated: Wilcoxon rank sum test. n = 5 (control group) or 6 (irradiated groups). I–L) The abundances of most varied strain bacteria in male I, J) and female K,L) mice was assessed using 16S high‐throughput sequencing after irradiation at day 7. Significant differences are indicated: Wilcoxon rank sum test. n = 5 (control group) or 6 (irradiated groups).
Figure 5
Figure 5
Simvastatin and HFD administration shape intestinal bacterial structure at day 14 after TAI in a sexual‐dependent fashion. A,B) The observed species number A) and Chao1 diversity index B) of enteric bacteria in male mice was measured by 16S rRNA high‐throughput sequencing at 14 d after TAI exposure. Significant differences are indicated: Wilcoxon rank sum test. n = 5 (control group) or 6 (irradiated groups). C,D) The observed species number C) and Chao1 diversity index D) of enteric bacteria in female mice was measured by 16S rRNA high‐throughput sequencing at 14 d after TAI exposure. Significant differences are indicated: Wilcoxon rank sum test. n = 5 (control group) or 6 (irradiated groups). E,F) PCoA were performed to assess the alteration of gut bacteria taxonomic profile from male E) and female F) mice after TAI at day 14. n = 5 (control group) or 6 (irradiated groups). G,H) The β diversity of intestinal bacteria was compared by weighted unifrac analysis. Significant differences are indicated: Wilcoxon rank sum test. n = 5 (control group) or 6 (irradiated groups). I–L) The abundances of most varied strain bacteria in male I,J) and female K,L) mice was examined using 16S high‐throughput sequencing after TAI at day 14. Significant differences are indicated: Wilcoxon rank sum test. n = 5 (control group) or 6 (irradiated groups).
Figure 6
Figure 6
The optimal therapeutic options reprogram radiation‐shaped gene expression profile of mice small intestines. In this experiment, male mice were divided into three groups. One group was exposed to 12 Gy TAI, one group was treated with simvastatin following 12 Gy TAI exposure, another group was control. Female mice were also divided into three groups. One group was exposed to 12 Gy TAI, one group was fed with HFD following 12 Gy TAI exposure, another group was control. Small intestine tissues were obtained at day 21 after irradiation. A–D) Cluster analysis of differentially expressed miRNA of small intestine tissues from male A,B) and female C,D) mice. A: control group versus TAI group, B: simvastatin group versus TAI group, C: control group versus TAI group, D: HFD group versus TAI group. E–L) Bioinformatics analysis of different proteins clustered into pathways of small intestine tissues from male and female mice through KEGG. M,N) Kaplan–Meier analysis of overall survival rate of prostatic cancer and ovarian cancer patients. P < 0.05 by log‐rank test between the patients with high and low expression of HMGCR.
Figure 7
Figure 7
Gut microbiota contributes to the radioprotective effects of simvastatin and HFD in male mice. The mice were housed with antibiotic mixture (ABX) in drinking water. A,B) Photographs of thymuses A) and spleens B) from male mice in the four groups, the thymuses and spleens were obtained at day 21 after 4 Gy TBI. n = 18 per group. C) The level of IL‐6 in PB was examined. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. D) Photograph of dissected colon from male mice in the four groups. E) The morphology of the small intestine from male mice was shown by H&E and PAS staining. The black arrows point to the goblet cells. F) The level of IL‐6 in small intestine tissues was examined by ELISA. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. G–I) The expression levels of Glut1 G), MDR1 H), and Nrf2 I) were examined in small intestine tissues by quantitative PCR. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. J) The level of MDA was assessed in small intestine tissue. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. K) The level of FITC‐dextran in PB was assessed. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. L) The expression levels of miRNAs were examined in small intestine tissues by quantitative PCR. Significant differences are indicated by Student's t‐test between each two cohort, n = 18 per group.
Figure 8
Figure 8
Gut microbiota contributes to the radioprotective effects of simvastatin and HFD in female mice. The mice were housed with antibiotic mixture (ABX) in drinking water. A,B) Photographs of thymuses A) and spleens B) from female mice in the four groups, the thymuses and spleens were obtained at day 21 after 4 Gy TBI. n = 18 per group. C) The level of IL‐6 in PB was examined. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. D) Photograph of dissected colon from female mice in the four groups. E) The morphology of the small intestine from female mice was shown by H&E and PAS staining. The black arrows point to the goblet cells. F) The level of IL‐6 in small intestine tissues was examined by ELISA. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. G–I) The expression levels of Glut1 G), MDR1 H), and Nrf2 I) were examined in small intestine tissues by quantitative PCR. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. J) The level of MDA was assessed in small intestine tissue. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. K) The level of FITC‐dextran in PB was assessed. Significant differences are indicated: *P < 0.05 by Student's t‐test between each two cohort, n = 18 per group. L) The expression levels of miRNAs were examined in small intestine tissues by quantitative PCR. Significant differences are indicated by Student's t‐test between each two cohort, n = 18 per group.
Figure 9
Figure 9
The curative effects of simvastatin and HFD mitigating radiation toxicity base on gut microbiota composition pattern. FMT was performed to male (or female) mice using fecal pellets from female (or male) mice for 14 d. Before 7 Gy TBI exposure, the fecal pellets of recipients were collected and assessed measured by 16S rRNA high‐throughput sequencing. A,B) The observed species number A) and Chao1 diversity index B) of enteric bacteria in male recipients was measured. Significant differences are indicated: Wilcoxon rank sum test. n = 5 per group. C,D) The observed species number C) and Chao1 diversity index D) of enteric bacteria in female recipients was measured. Significant differences are indicated: Wilcoxon rank sum test. n = 5 per group. E,G) PCoA were used to examined the alteration of intestinal bacteria taxonomic pattern from male E) and female G) recipients. n = 5 per group. F,H) The β diversity of enteric bacteria was compared by weighted unifrac analysis. Significant differences are indicated: Wilcoxon rank sum test. n = 5 per group. I,J) Kaplan–Meier analysis I) and body weight measurement J) of male recipients after 7 Gy TBI, n = 18 per group; *P < 0.05, **P < 0.01 by Student's t‐test between simvastatin‐treated group and control. K,L) Kaplan–Meier analysis K) and body weight measurement L) of female recipients after 7 Gy TBI, n = 18 per group.

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