# Phocaeicola coprophilus‐Derived 6‐Methyluracil Attenuates Radiation‐Induced Intestinal Fibrosis by Suppressing the IDO1‐Kynurenine‐AHR Axis

## TL;DR

A gut bacterium and its metabolite can reduce intestinal fibrosis caused by radiation by blocking a harmful signaling pathway.

## Contribution

Identifies Phocaeicola coprophilus and its metabolite 6-methyluracil as potential therapies for radiation-induced intestinal fibrosis.

## Key findings

- Radiation reduces Phocaeicola coprophilus and its metabolite 6-methyluracil.
- IDO1-Kyn-AHR signaling is suppressed by P. coprophilus or 6-methyluracil.
- Restoration of P. coprophilus or 6-methyluracil mitigates radiation-induced fibrosis.

## Abstract

Therapeutic options for radiation‐induced intestinal fibrosis (RIF) remain limited. This study reveals that intestinal kynurenine (Kyn) is persistently elevated after radiation and correlates with fibrosis severity in both murine models and human rectal cancer samples. Exogenous Kyn exacerbated RIF, whereas inhibition of indoleamine 2,3‐dioxygenase 1 (IDO1) attenuated fibrotic progression. Mechanistically, Kyn activates the aryl hydrocarbon receptor (AHR) to promote fibroblast activation and fibrosis. Antibiotic depletion of gut microbiota abrogates radiation‐induced IDO1‐Kyn upregulation and protects against RIF. Conversely, fecal microbiota transplantation from irradiated mice recapitulates the elevated IDO1‐Kyn phenotype. Metagenomic analysis identify radiation‐induced depletion of Phocaeicola coprophilus (P. coprophilus), whose abundance inversely correlates with Kyn levels. Supplementation with live P. coprophilus suppresses IDO1‐Kyn signaling and ameliorates RIF. Untargeted metabolomics further show that radiation reduces 6‐methyluracil, a metabolite derived from P. coprophilus. Exogenous 6‐methyluracil replenishment inhibits repression of the IDO1‐Kyn axis and mitigates fibrosis. Together, these findings define a microbiota–metabolite–host pathway in which radiation depletes P. coprophilus, leading to loss of 6‐methyluracil and derepression of the IDO1‐Kyn‐AHR axis, thereby driving fibrogenesis. Restoration of either P. coprophilus or its metabolite 6‐methyluracil represents a promising therapeutic strategy against RIF.

IR‐induced dysbiosis depletes P. coprophilus and its metabolite 6‐methyluracil, leading to disinhibition of the IDO1‐Kyn‐AHR axis. This results in sustained fibroblast activation and collagen deposition, driving radiation induced intestinal fibrosis.