# Kynurenine mediates the chemotherapy-induced intestinal toxicity through modulation of gut microbiota

## TL;DR

This study finds that a metabolite called L-kynurenine, produced by immune cells, worsens gut damage from chemotherapy by altering gut bacteria and triggering cell death.

## Contribution

The study identifies L-kynurenine from myeloid cells as a mediator of chemotherapy-induced gut toxicity and proposes it as a therapeutic target.

## Key findings

- L-kynurenine levels are elevated in patients with severe chemotherapy-induced intestinal toxicity.
- L-kynurenine causes gut dysbiosis, including loss of Lactobacillus johnsonii, and activates the TNFα/JNK pathway.
- Reducing L-kynurenine mitigates chemotherapy-induced intestinal injury in models.

## Abstract

Chemotherapy-induced intestinal toxicity is a major dose-limiting complication, but the underlying mechanisms linking systemic metabolism to localized gut damage are poorly understood. Here we show that serum L-kynurenine, a tryptophan metabolite, is elevated in patients with severe oxaliplatin-induced intestinal toxicity. Accumulation of L-kynurenine is driven by IFNγ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) in myeloid cells. Using scRNA-seq and myeloid cell-specific knockout models, we confirm that myeloid cell-derived L-kynurenine exacerbates toxicity. Critically, L-kynurenine accumulation drives gut dysbiosis, characterized by the loss of Lactobacillus johnsonii, and subsequently activates the TNFα/JNK pathway, leading to intestinal epithelial apoptosis. Pharmacological inhibition or engineered reduction of L-kynurenine mitigates chemotherapy-induced intestinal injury. Our findings reveal an important role of L-kynurenine from myeloid cells in chemotherapy tolerance and propose its targeting as a potential therapeutic strategy.

Chemotherapy-induced intestinal toxicity limits treatment efficacy. Here, the authors show that myeloid-derived L-kynurenine exacerbates this damage by depleting Lactobacillus johnsonii, which activates the TNFα/JNK pathway to drive epithelial apoptosis.