Tryptophan indole metabolites reduce anastomotic leakage through aryl hydrocarbon receptor-driven interleukin-22 production.

BACKGROUND: Colorectal cancer often requires surgical resection of the tumor and an anastomosis. Anastomotic leakage (AL) occurs in 2.8-30% of patients which increases postoperative morbidity and complications. The preoperative microbiome composition is implicated in AL. Recent studies have shown that microbial tryptophan (Trp) metabolism into aryl hydrocarbon receptor (AhR) indole-derivatives contributes to intestinal tissue healing. Here, we addressed the role of Trp and its metabolites in AL in a CRC patient cohort and a colon-anastomosis mouse model.

METHODS: Targeted quantitative metabolomics was performed in preoperative fecal samples from patients with CRC recruited in the REVEAL cohort (n = 388), including 19 AL cases. Anastomotic Healing (AH) was tested in a mouse model using wildtype, AhR, VillinAhr, and IL-22 drug-targeting to evaluate the role of AhR and IL-22 in AL.

RESULTS: Fifty-two of the 388 patients with available preoperative fecal samples were matched for AH/AL occurrence (AL, n = 19; AH, n = 33). Amongst Trp metabolites, indole-3-acetic acid was significantly reduced in AL compared to matched AH male patients. AhR mice displayed more severe AL, reduced IL-22 expression, and a marked loss of IL-22-expressing type 3 ILCs compared to wildtype mice. Neutralizing IL-22 antibody augmented AL in wildtype mice, while IL-22Fc application ameliorated AL in AhR mice. AhR agonism failed to rescue healing under IL-22 deficiency. Furthermore, low-Trp diet-fed wildtype mice exhibited reduced fecal concentration of AhR agonists and, AhR-agonist producing bacteria, and augmented AL. This phenotype was prevented by dietary supplementation with the AhR agonist indole-3-carbinol.

CONCLUSION: Stimulation of the AhR/IL-22 by synthetic agonists or dietary-derived Trp-metabolites can prevent AL.

Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 41707749