Gut Microbiota-derived Indole 3-propionic Acid Protects Against Ionizing Radiation-induced Toxicity

Cancer is a leading cause of death throughout the world.Despite considerable advances in understanding the molecular basis of abdominal and pelvic neoplasms,abdominal and pelvic cancers,such as colorectal cancer,prostate cancer and cervical cancer,remain the most common form of cancer leading to tumor-related mortality globally.As a common feasible therapy approach,radiotherapy represents the most effective therapeutic regimen for patients with cancer and improves their survival.However,the final outcome of this single treatment modality is still uncertain,with a high risk of recurrence among patients with unfavorable side effects.After radiation exposure,a complex array of clinical complications are accompanied,such as bone marrow toxicity(hematopoietic syndrome)and gastrointestinal toxicity(GI syndrome),which are collectively known as acute radiation syndrome.Even for healthy populations,unwanted radiological or nuclear exposure remains a serious public health risk.Unfortunately,effective countermeasure agents to attenuate radiation-caused injury in exposed individuals remain an unmet medical need.In this study,we sought to investigate whether indole-3-propionic acid(IPA),a bacterial-mediated production from tryptophan,might ameliorate radiation-mediated injury using mouse models.Severe radiation exposure causes acute radiation syndrome requiring effective therapy.Fecal microbiota transplantation(FMT)has been proved to mitigate radiation-induced toxicity.However,the underlying mechanisms remain incompletely characterized.We reported that microbial-specific indole 3-propionic acid(IPA),a metabolite of tryptophan in the gastrointestinal(GI)tract,was capable of fighting against radiation-associated toxicity by retaining acyl-CoA binding protein(ACBP)through transcription factor pregnane X receptor(PXR).Specifically,I PA-treated mice represented ameliorative myelosuppression,lower inflammatory levels,improved GI function and epithelial integrity following radiation without precipitating tumour growth in male and female mice.16S rRNA and subsequent analyses showed irradiated mice harbored a disordered enteric bacterial pattern,which was preserved after IPA administration.Furthermore,the mice were treated with antibiotics(ABX)to clear gut microbes which indicating that IPA protects against radiation-induced G1 injuries partly based on gut microbes.iTRAQ analysis presented IPA reprogrammed radiation-shifted protein expression profile in the small intestine.PXR/ACBP signaling deletion impaired the radioprotection of IPA in vitro and in vivo.The irradiated mice with ACBP or PXR deletion showed deteriorative GI tract injuries characterized by shorter colon length,higher inflammation and ROS levels,fewer intestinal villi and goblet cells,worsen the GI tract function and epithelial integrity,indicating that IPA performs radioprotection to GI tract partly depending on PXR/ACBP signaling.Together,our findings underpin that IPA is an important microbiota metabolite carrying radio-protective effects.Clinically,IPA might be employed as a microbiome-based therapeutic approach toward radioactive disease,and cancer patients might replenish IPA to alleviate clinical complications after radiotherapy without precipitating tumour growth.Importantly,ACBP is a novel target for the development of radioprotective drugs.