Gut microbiota-derived indole 3-propionic acid protects against radiation toxicity via retaining acyl-CoA-binding protein

Abstract

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.

The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases

“…The major function of the gut microbiota is to help in the harvesting of nutrients and energy from our diet. Moreover, it participates in the development of a host’s immune system, brain, and behavior; protects against pathogens; and is a factory of bioactive compounds [ 29 , 30 ].…”

Radiotherapy and the gut microbiome: facts and fiction

“…Additionally, FMT is also shown to be an efficacious remedy to mitigate acute radiation syndrome. Recent study [ 100 ] confirmed that indole 3-propionic acid is a key intestinal microbiota metabolite corroborating the therapeutic effects of FMT to radiation toxicity.…”

Acute Radiation Syndrome and the Microbiome: Impact and Review

“…To exploit the many microbiota and functional changes observed with animal models in response to radiation, studies have been done to evaluate the usefulness of microbiota-derived short-chain fatty acids and other metabolic products as potential MCMs, to either prevent or mitigate radiation-induced GI injury. In a study in which FMT was given to irradiated mice, analysis of fecal pellets showed that a microbial molecule-indole 3-propionic acid (IPA)-was present at high levels (Xiao et al, 2020). Believing that this molecule could be responsible for the observed radiation protection obtained with FMT, oral IPA alone was provided to another group of irradiated animals.…”

“…Other studies found oral gavage of IPA and microbiota-derived valeric acid (VA) provided protection against up to 7 Gy, and, in the case of VA, mitigated GI radiation injury when given post-TAI (12 Gy). VA was found to prevent intestinal inflammation and dysfunction, and maintain microbiota compositional patterns Xiao et al, 2020).…”