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

Serum L-kynurenine is elevated in patients with severe oxaliplatin-induced intestinal toxicity.

• L-kynurenine is a tryptophan metabolite identified as elevated in the serum of affected patients.
• The elevation was associated specifically with severe intestinal toxicity, a major dose-limiting complication of chemotherapy.
• This finding was established in a clinical patient cohort receiving oxaliplatin-based chemotherapy.

L-kynurenine accumulation is driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) in myeloid cells.

• IFN-γ signaling was identified as the upstream mediator inducing IDO1 expression.
• IDO1 is the enzyme responsible for converting tryptophan to L-kynurenine.
• Myeloid cells were identified as the cellular source of the elevated L-kynurenine.

Myeloid cell-specific knockout models confirm that myeloid cell-derived L-kynurenine exacerbates chemotherapy-induced intestinal toxicity.

• Single-cell RNA sequencing (scRNA-seq) was used to characterize the myeloid cell populations involved.
• Myeloid cell-specific knockout models were generated to isolate the contribution of myeloid-derived L-kynurenine.
• These models confirmed a causal role for myeloid cell-derived L-kynurenine in exacerbating intestinal toxicity.

L-kynurenine accumulation drives gut dysbiosis characterized by the loss of Lactobacillus johnsonii.

• L-kynurenine accumulation was linked to compositional changes in the gut microbiota.
• The specific loss of Lactobacillus johnsonii was identified as a key feature of the dysbiosis.
• This microbiota disruption was positioned as an intermediary step between L-kynurenine elevation and intestinal epithelial damage.

Gut dysbiosis induced by L-kynurenine activates the TNFα/JNK pathway, leading to intestinal epithelial apoptosis.

• Loss of Lactobacillus johnsonii was upstream of TNFα/JNK pathway activation.
• Activation of the TNFα/JNK signaling pathway resulted in intestinal epithelial cell apoptosis.
• This mechanistic cascade connects systemic metabolic changes to localized gut epithelial damage.

Pharmacological inhibition or engineered reduction of L-kynurenine mitigates chemotherapy-induced intestinal injury.

• Both pharmacological inhibition approaches and engineered reduction strategies targeting L-kynurenine were tested.
• Reduction of L-kynurenine levels resulted in mitigation of chemotherapy-induced intestinal injury.
• These findings propose L-kynurenine targeting as a potential therapeutic strategy to improve chemotherapy tolerance.