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Project description: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.
| S-EPMC6839645 | biostudies-literature
Project description:Accidental or iatrogenic ionizing radiation exposure precipitates acute and chronic radiation injuries. Traditional paradigm of mitigating radiotherapy-associated side effects has ignored the gender-specific dimorphism of patients. Here we examined the effects of sexual dimorphism on therapeutic agent efficiencies in murine models. High-throughput sequencing showed that different treatments preserved miRNA expression profile in small intestines of male or female mice, respectively. Collectively, our observations demonstrate that therapeutic strategy efficiencies for radiation toxicity might be dependent on the gender of patients. We aim to uncover the underlying mechanisms by which simvastatin or high fat diet fights against radiotherapy-induced gastrointestinal tract toxicity for male or female mice. The mice were exposed to 12 Gy total abdominal irradiation (TAI), then treated with simvastatin for male mice or fed with high fat diet for female mice. The small intestine tissues were extracted from male mice without TAI, exposed to TAI only, and exposed to TAI combined with simvastatin treatment as one cohort, and from female mice without TAI, exposed to TAI only, and exposed to TAI combined with high fat diet feeding as the other cohort.
2020-01-25 | GSE126506 | GEO
Project description:Accidental or iatrogenic ionizing radiation exposure precipitates acute and chronic radiation injuries. Traditional paradigm of mitigating radiotherapy-associated side effects has ignored the gender-specific dimorphism of patients. Here we examined the effects of sexual dimorphism on therapeutic agent efficiencies in murine models. High-throughput sequencing of host mRNA showed that different treatments reprogrammed the spectrum of mRNA expression in small intestines of male or female mice, respectively. Collectively, our observations demonstrate that therapeutic strategy efficiencies for radiation toxicity might be dependent on the gender of patients. We aim to uncover the underlying mechanisms by which simvastatin or high fat diet fights against radiotherapy-induced gastrointestinal tract toxicity for male or female mice. The mice were exposed to 12 Gy total abdominal irradiation (TAI), then treated with simvastatin for male mice or fed with high fat diet for female mice. The small intestine tissues were extracted from male mice without TAI, exposed to TAI only, and exposed to TAI combined with simvastatin treatment as one cohort, and from female mice without TAI, exposed to TAI only, and exposed to TAI combined with high fat diet feeding as the other cohort.
2020-01-25 | GSE126507 | GEO
Project description:Sexual dimorphism of gut microbiota dictates therapeutics efficacy of radiation injuries
| PRJNA522239 | ENA
Project description:Sexual dimorphism of gut microbiota dictates therapeutics efficacy of radiation injuries [RNA-seq]
| PRJNA522242 | ENA
Project description:Sexual dimorphism of gut microbiota dictates therapeutics efficacy of radiation injuries [miRNA-seq]
| PRJNA522243 | ENA
Project description:BackgroundGonadal steroid hormones have been suggested as the underlying mechanism responsible for the sexual dimorphism observed in metabolic diseases. Animal studies have also evidenced a causal role of the gut microbiome and metabolic health. However, the role of sexual dimorphism in the gut microbiota and the potential role of the microbiome in influencing sex steroid hormones and shaping sexually dimorphic susceptibility to disease have been largely overlooked. Although there is some evidence of sex-specific differences in the gut microbiota diversity, composition, and functionality, the results are inconsistent. Importantly, most of these studies have not taken into account the gonadal steroid status. Therefore, we investigated the gut microbiome composition and functionality in relation to sex, menopausal status, and circulating sex steroids.ResultsNo significant differences were found in alpha diversity indices among pre- and post-menopausal women and men, but beta diversity differed among groups. The gut microbiota from post-menopausal women was more similar to men than to pre-menopausal women. Metagenome functional analyses revealed no significant differences between post-menopausal women and men. Gonadal steroids were specifically associated with these differences. Hence, the gut microbiota of pre-menopausal women was more enriched in genes from the steroid biosynthesis and degradation pathways, with the former having the strongest fold change among all associated pathways. Microbial steroid pathways also had significant associations with the plasma levels of testosterone and progesterone. In addition, a specific microbiome signature was able to predict the circulating testosterone levels at baseline and after 1-year follow-up. In addition, this microbiome signature could be transmitted from humans to antibiotic-induced microbiome-depleted male mice, being able to predict donor's testosterone levels 4 weeks later, implying that the microbiota profile of the recipient mouse was influenced by the donor's gender. Finally, obesity eliminated most of the differences observed among non-obese pre-menopausal women, post-menopausal women, and men in the gut microbiota composition (Bray-Curtis and weighted unifrac beta diversity), functionality, and the gonadal steroid status.ConclusionsThe present findings evidence clear differences in the gut microbial composition and functionality between men and women, which is eliminated by both menopausal and obesity status. We also reveal a tight link between the gut microbiota composition and the circulating levels of gonadal steroids, particularly testosterone. Video Abstract.
| S-EPMC7504665 | biostudies-literature
Project description:Animal nutrition is profoundly influenced by the gut microbiota, but knowledge of the scope and core mechanisms of the underlying animal-microbiota interactions is fragmentary. To investigate the nutritional traits shaped by the gut microbiota of Drosophila, we determined the microbiota-dependent response of multiple metabolic and performance indices to systematically varied diet composition. Diet-dependent differences between Drosophila bearing its unmanipulated microbiota (conventional flies) and experimentally deprived of its microbiota (axenic flies) revealed evidence for: microbial sparing of dietary B vitamins, especially riboflavin, on low-yeast diets; microbial promotion of protein nutrition, particularly in females; and microbiota-mediated suppression of lipid/carbohydrate storage, especially on high sugar diets. The microbiota also sets the relationship between energy storage and body mass, indicative of microbial modulation of the host signaling networks that coordinate metabolism with body size. This analysis identifies the multiple impacts of the microbiota on the metabolism of Drosophila, and demonstrates that the significance of these different interactions varies with diet composition and host sex.
| S-EPMC4037322 | biostudies-literature
Project description:BackgroundHematopoietic and intestinal systems side effects are frequently found in patients who suffered from accidental or medical radiation exposure. In this case, we investigated the effects of gut microbiota produced-valeric acid (VA) on radiation-induced injuries.MethodsMice were exposed to total body irradiation (TBI) or total abdominal irradiation (TAI) to mimic accidental or clinical scenarios. High-performance liquid chromatography (HPLC) was performed to assess short-chain fatty acids (SCFAs) in fecal pellets. Oral gavage with VA was used to mitigate radiation-induced toxicity. Gross examination was performed to assess tissue injuries of thymus, spleen and small intestine. High-throughput sequencing was used to characterize the gut microbiota profile. Isobaric tags for relative and absolute quantitation (iTRAQ) were performed to analyze the difference of protein profile. Hydrodynamic-based gene delivery assay was performed to silence KRT1 in vivo.ResultsVA exerted the most significant radioprotection among the SCFAs. In detail, VA replenishment elevated the survival rate of irradiated mice, protected hematogenic organs, improved gastrointestinal (GI) tract function and intestinal epithelial integrity in irradiated mice. High-throughput sequencing and iTRAQ showed that oral gavage of VA restored the enteric bacteria taxonomic proportions, reprogrammed the small intestinal protein profile of mice following TAI exposure. Importantly, keratin 1 (KRT1) played a pivotal role in the radioprotection of VA.ConclusionsOur findings provide new insights into gut microbiota-produced VA and underpin that VA might be employed as a therapeutic option to mitigate radiation injury in pre-clinical settings.
| S-EPMC7524389 | biostudies-literature
Project description:BackgroundUnderstanding the mechanism of the sexual dimorphism in susceptibility to obesity and metabolic syndrome (MS) is important for the development of effective interventions for MS.ResultsHere we show that gut microbiome mediates the preventive effect of estrogen (17?-estradiol) on metabolic endotoxemia (ME) and low-grade chronic inflammation (LGCI), the underlying causes of MS and chronic diseases. The characteristic profiles of gut microbiome observed in female and 17?-estradiol-treated male and ovariectomized mice, such as decreased Proteobacteria and lipopolysaccharide biosynthesis, were associated with a lower susceptibility to ME, LGCI, and MS in these animals. Interestingly, fecal microbiota-transplant from male mice transferred the MS phenotype to female mice, while antibiotic treatment eliminated the sexual dimorphism in MS, suggesting a causative role of the gut microbiome in this condition. Moreover, estrogenic compounds such as isoflavones exerted microbiome-modulating effects similar to those of 17?-estradiol and reversed symptoms of MS in the male mice. Finally, both expression and activity of intestinal alkaline phosphatase (IAP), a gut microbiota-modifying non-classical anti-microbial peptide, were upregulated by 17?-estradiol and isoflavones, whereas inhibition of IAP induced ME and LGCI in female mice, indicating a critical role of IAP in mediating the effects of estrogen on these parameters.ConclusionsIn summary, we have identified a previously uncharacterized microbiome-based mechanism that sheds light upon sexual dimorphism in the incidence of MS and that suggests novel therapeutic targets and strategies for the management of obesity and MS in males and postmenopausal women.
| S-EPMC6234624 | biostudies-literature