Abstract
BackgroundWe 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.ResultsFMT 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, IPA-treated 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 radiation-reprogrammed protein expression profile in the small intestine. Importantly, shRNA interference and hydrodynamic-based 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.ConclusionsThese 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.5xbhwSC1V4FsDQpg8AwjrSVideo abstract.
Highlights
We have proved fecal microbiota transplantation (FMT) is an efficacious remedy to mitigate acute radiation syndrome (ARS); the mechanisms remain incompletely characterized
We compared the frequency of Clostridium in mouse fecal extracts based on our previous study [29]. 16S ribosomal RNA (rRNA) sequencing analysis showed that total abdominal irradiation exposure lessened the level of Clostridium, while GI toxicity rehabilitation was enmeshed with elimination of the shifts (Fig. 1c)
After exposure to 7.2 Gy total body irradiation (TBI), the male animal survival rate was decreased by 60% in the control vehicle group, but it was decreased by 50% or 30% in irradiation male animals receiving 3.75 or 7.5 mg/ml concentration of indole 3-propionic acid (IPA)
Summary
We have proved fecal microbiota transplantation (FMT) is an efficacious remedy to mitigate acute radiation syndrome (ARS); the mechanisms remain incompletely characterized. 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. As a common feasible therapy approach, about 50–60% of cancer patients receive radiotherapy during their treatment courses [4]. Radiotherapy represents the most effective therapeutic regimen for patients with cancer and improves their survival. The final outcome of this single treatment modality is still uncertain, with a high risk of recurrence among patients with unfavorable side effects [5]. Effective countermeasure agents to attenuate ARS in exposed individuals remain an unmet medical need
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
