Background: We have proved fecal microbiota transplantation (FMT) is an efficacious remedy to mitigate acute radiation syndrome (ARS); however, the mechanisms remain incompletely characterized. Here, we aimed to tease apart the gut microbiota-produced metabolites, underpin the therapeutic effects of FMT to radiation injuries, and elucidate the underlying molecular mechanisms. Results: FMT elevated the level of microbial-derived indole 3-propionic acid (IPA) in fecal pellets from irradiated mice. IPA replenishment via oral route attenuated hematopoietic system and gastrointestinal (GI) tract injuries intertwined with radiation exposure without precipitating tumor growth in male and female mice. Specifically, IPAtreated mice represented a lower system inflammatory level, recuperative hematogenic organs, catabatic myelosuppression, improved GI function, and epithelial integrity following irradiation. 16S rRNA gene sequencing and subsequent analyses showed that irradiated mice harbored a disordered enteric bacterial pattern, which was preserved after IPA administration. Notably, iTRAQ analysis presented that IPA replenishment retained radiationreprogrammed protein expression profile in the small intestine. Importantly, shRNA interference and hydrodynamicbased gene delivery assays further validated that pregnane X receptor (PXR)/acyl-CoA-binding protein (ACBP) signaling played pivotal roles in IPA-favored radioprotection in vitro and in vivo. Conclusions: These evidences highlight that IPA is a key intestinal microbiota metabolite corroborating the therapeutic effects of FMT to radiation toxicity. Owing to the potential pitfalls of FMT, IPA might be employed as a safe and effective succedaneum to fight against accidental or iatrogenic ionizing ARS in clinical settings. Our findings also provide a novel insight into microbiome-based remedies toward radioactive diseases.

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BackgroundBreast cancer (BRCA) is the leading cause of cancer‐related death in women worldwide. Pre‐ and postoperative radiotherapy play a pivotal role in BRCA treatment but its efficacy remains limited and plagued by the emergence of radiation resistance, which aggravates patient prognosis. The long noncoding RNA (lncRNA)‐implicated mechanisms underlying radiation resistance are rarely reported. The aim of this study was to determine whether lncRNA HOX transcript antisense RNA (HOTAIR) modulated the radiosensitivity of breast cancer through HSPA1A.MethodsA Gammacell 40 Exactor was used for irradiation treatment. Bioinformatic tools and luciferase reporter assay were adopted to explore gene expression profile and demonstrate the interactions between lncRNA, miRNA and target mRNA 3′‐untranslated region (3′‐UTR). The expression levels of certain genes were determined by real‐time PCR and western‐blot analyses. in vitro and in vivo functional assays were conducted by cell viability and tumorigenicity assays.ResultsThe levels of oncogenic lncRNA HOTAIR were positively correlated with the malignancy of BRCA but reversely correlated with the radiosensitivity of breast cancer cells. Moreover, the expression levels of HOTAIR were positively associated with those of heat shock protein family A (Hsp70) member 1A (HSPA1A) in clinical BRCA tissues and HOTAIR upregulated HSPA1A at the mRNA and protein levels in irradiated BRCA cells. Mechanistically, miR‐449b‐5p restrained HSPA1A expression through targeting the 3′‐UTR of HSPA1A mRNA, whereas HOTAIR acted as a competing sponge to sequester miR‐449b‐5p and thereby relieved the miR‐449b‐5p‐mediated HSPA1A repression. Functionally, HOTAIR conferred decreased radiosensitivity on BRCA cells, while miR‐449b‐5p overexpression or HSPA1A knockdown abrogated the HOTAIR‐enhanced BRCA growth under the irradiation exposure both in vitro and in vivo.ConclusionsLncRNA HOTAIR facilitates the expression of HSPA1A by sequestering miR‐449b‐5p post‐transcriptionally and thereby endows BRCA with radiation resistance.Key pointsTherapeutically, HOTAIR and HSPA1A may be employed as potential targets for BRCA radiotherapy. Our findings shed new light into the mechanism by which lncRNAs modulate the radiosensitivity of tumors.

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.

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