Gut microbial metabolite facilitates colorectal cancer development via ferroptosis inhibition
Menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel l'acide trans-3-indoléacrylique, un métabolite du tryptophane issu de la bactérie Peptostreptococcus anaerobius, favorise la carcinogenèse colorectale via l'inhibition de la ferroptose
The gut microbiota play a pivotal role in human health. Emerging evidence indicates that gut microbes participate in the progression of tumorigenesis through the generation of carcinogenic metabolites. However, the underlying molecular mechanism is largely unknown. In the present study we show that a tryptophan metabolite derived from Peptostreptococcus anaerobius, trans-3-indoleacrylic acid (IDA), facilitates colorectal carcinogenesis. Mechanistically, IDA acts as an endogenous ligand of an aryl hydrocarbon receptor (AHR) to transcriptionally upregulate the expression of ALDH1A3 (aldehyde dehydrogenase 1 family member A3), which utilizes retinal as a substrate to generate NADH, essential for ferroptosis-suppressor protein 1(FSP1)-mediated synthesis of reduced coenzyme Q10. Loss of AHR or ALDH1A3 largely abrogates IDA-promoted tumour development both in vitro and in vivo. It is interesting that P. anaerobius is significantly enriched in patients with colorectal cancer (CRC). IDA treatment or implantation of P. anaerobius promotes CRC progression in both xenograft model and ApcMin/+ mice. Together, our findings demonstrate that targeting the IDA–AHR–ALDH1A3 axis should be promising for ferroptosis-related CRC treatment.
Nature Cell Biology 2024